Amino-substituted sulfonanilides and derivatives thereof for treating proliferative disorders

ABSTRACT

Compounds useful as antiproliferative agents, including, for example, anticancer agents, are provided according to formula I: wherein: Ar, X, X 1 , g, R and R 3  are as defined herein.

FIELD OF THE INVENTION

The invention relates to compositions and methods for the treatment ofproliferative disorders, including but not limited to cancer.

BACKGROUND OF THE INVENTION

α-β-Unsaturated Sulfonamides

Cancer remains a leading-cause of mortality in the United States and inthe world. To be useful, a new chemotherapeutic agent should have a widespectrum of activity and significant therapeutic index.Styrene-ω-sulfonanilide has been prepared by reacting styrylsulfonylchloride with aniline (Bordwell et al., J. Amer. Chem. Soc. 68:139,1946). This and certain other styrene-ω-sulfonanilides have beenprepared by Knoevenagel-type synthesis as possible chemosterilantsagainst the common house fly Musca domestica L. (Oliver et al.,Synthesis 321-322, 1975).

U.S. Pat. No. 4,035,421 to Snyder, Jr. describes the preparation ofN-(3,4-dichlorophenyl)-2-phenylethenesulfonamide and its use as anantibacterial agent.

The styrene-ω-sulfonanilides 3′-hydroxy-4-nitrostyrene-βsulfonanilide,3′-hydroxy-2-nitrostyrene-β-sulfonanilide and5′-hydroxy-2′-methyl-4-nitrostyrene-β-sulfonanilide were utilized asintermediates in the preparation of certain stilbenes by Waldau et al.Angew. Chem., It. Ed. Engl. 11(9):826-8 (1972). Thestyrene-ω-sulfonanilides 3′-hydroxy-3-nitrostyrene-β-sulfonanilide and5′-hydroxy-2′-methyl-4-nitrostyrene-β-sulfonanilide have been utilizedin the preparation of stilbenes used as dyes (DE 2118493-Farbenfab AG).

Aswarthamma et al., Chimica Acta Turcica 24:7-10 (1996) disclose thepreparation of certain trans-(1-aryl-(2-anilinesulphonyl)ethylenes. Nobiological activity is set forth for the compounds. Touarti et al., JSoc. Alger. Chim. 6(1):39-52 (1996) disclose the preparation of certainα,β-unsaturated sulfonamides for inhibition of coniferyl alcoholdehydrogenase (CADH).

Except for the isolated teaching of antibacterial activity ofN-(3,4-dichlorophenyl)-2-phenylethenesulfonamide, no usefulpharmaceutical activity has been proposed for the limited numbers ofα,β-unsaturated sulfonamides known to the prior art. In particular, noanti-cell proliferation or anticancer utility has been proposed for thisclass of compounds.

New cell antiproliferative agents, and anticancer therapeutics inparticular, are needed which are useful in inhibiting proliferation ofand/or killing cancer cells. In particular, such agents are needed whichare selective in the killing of proliferating cells such as tumor cells,but not normal cells. Antineoplasitc agents are needed which areeffective against a broad range of tumor types.

SUMMARY OF THE INVENTION

It is an object of the invention to provide compounds, compositions andtherapeutic methods. The biologically active compounds are in the formof amino substituted sulfonanilides, and salts thereof.

It is an object of the invention to provide compounds, compositions andmethods for the treatment of cancer and other proliferative diseases.

It is an object of the invention to provide compounds which areselective in killing tumor cells but not normal cells.

It is an object of the invention to provide compounds, compositions andmethods for inducing neoplastic cells to selectively undergo apoptosis.

In one aspect, the invention is directed to novel compounds of formulaI:

wherein:

-   -   Ar is selected from the group consisting of substituted and        unsubstituted aryl, and substituted and unsubstituted        heteroaryl;    -   X is selected from the group consisting of (i) and (ii) below:    -   X¹ is selected from the group consisting of (i), (ii) and (iii)        below:    -   wherein X¹ is optionally protected with one or more chemical        protecting groups;    -   g is 0 or 1;    -   each M is a bivalent connecting group independently selected        from the group consisting of —(C₁-C₆)alkylene-,        (CH₂)_(a)—V—(CH₂)_(b)—, —(CH₂)_(d)—W—(CH₂)_(e)— and -Z-;    -   each y is independently selected from the group consisting of 0        and 1;    -   each V is independently selected from the group consisting of        —C(═O)—, (═O—, —C(═O)(C₁-C₆)perfluoroalkylene-, —C(═S)—, —S(═O),        —SO₂—, —C(═O)NR⁴—, —C(═S)NR⁴— and —SO₂NR⁴—;    -   each W is independently selected from the group consisting of        —NR⁴—, —O and —S—;    -   each a is independently selected from the group consisting of 0,        1, 2 and 3;    -   each b is independently selected from the group consisting of 0,        1, 2 and 3;    -   each d is independently selected from the group consisting of 1,        2 and 3;    -   each e is independently selected from the group consisting of 0,        1, 2 and 3;    -   wherein the absolute stereochemistry of -Z- is D or L or a        mixture of D and L;    -   R is selected from the group consisting of —H, (C₁-C₆)alkyl,        (C₁-C₆)alkoxy, (C₃-C₆)alkenyl, (C₂-C₆)heteroalkyl,        (C₃-C₆)heteroalkenyl, (C₂-C₆)hydroxyalkyl, substituted aryl,        unsubstituted aryl, substituted heterocyclic, unsubstituted        heterocyclic, substituted aryl(C₁-C₃)alkyl, unsubstituted        aryl(C₁-C₃)alkyl, substituted heterocyclic(C₁-C₃)alkyl and        unsubstituted heterocyclic(C₁-C₃)alkyl;    -   each R^(a) is independently selected from the group consisting        of —H, —CH₃, —(CH₂)₃—NH—C(NH₂)(═NH), —CH₂C(═O)NH₂, —CH₂COOH,        —CH₂SH, —(CH₂)₂C(═O)—NH₂, —(CH₂)₂COOH, —CH₂-(2-imidazolyl),        —CH(CH₃)—CH₂—CH₃, —CH₂CH(CH₃)₂, —(CH₂)₄—NH₂, —(CH₂)₂—S—CH₃,        phenyl, CH₂-phenyl, —CH₂—OH, —CH(OH)—CH₃, —CH₂-(3-indolyl),        —CH₂-(4-hydroxyphenyl), —CH(CH₃)₂ and —CH₂—CH₃; and includes        compounds wherein R¹ and R¹ combine to form a 5-, 6- or        7-membered heterocyclic ring;    -   each R¹ is independently selected from the group consisting of        —H, —(C₁-C₆)perfluoroalkyl, unsubstituted aryl, substituted        aryl, substituted heterocyclic, unsubstituted heterocyclic,        —CO₂R⁵, —C(═O)NR⁴ ₂, —CR⁴R⁶R⁷, —C(═NH)—NR⁴ ₂ and a monovalent        peptidyl moiety with a molecular weight of less than 1000;        provided that when y is 0 and R¹ is —CO₂R⁵, R⁵ is not —H;    -   each R² is independently selected from the group consisting of        —H, —(C₁-C₆)alkyl, and aryl(C₁-C₃)alkyl, wherein —R² and        -(M)_(y)-R¹ may optionally be linked covalently to form a 5-, 6-        or 7-membered substituted or unsubstituted heterocycle;    -   R³ is independently selected from —(C₁-C₆)alkyl;    -   each R⁴ is independently selected from the group consisting of        —H, and —(C₁-C₆)alkyl;    -   wherein:    -   when R⁴ and R¹ are bonded to the same nitrogen atom, R¹ and R⁴        may combine to form a heterocycle; and    -   when two R¹ groups are geminally bonded to the same nitrogen,        the two R⁴ groups may combine to form a heterocycle;    -   each R⁵ is independently selected from the group consisting of        —H, —(C₁-C₆)alkyl and —(C₁-C₆)acyl;    -   each R⁶ is independently selected from the group consisting of        —H, —(C₁-C₆)alkyl, —CO₂R⁵, —C(═O)R⁷, —OR⁵, —SR⁴, —(C₁-C₃)alkoxy,        —(C₁-C₃)alkylthio, guanidino, —NR⁴ ₂, phenyl, substituted        phenyl, heterocyclic, substituted heterocyclic and halogen;    -   each R⁷ is independently selected from the group consisting of        —H, halogen, —(C₁-C₆)alkyl, —NR⁴ ₂ and heterocycles containing        two nitrogen atoms; and    -   wherein the substituents for the substituted aryl and        substituted heterocyclic groups comprising or included within        Ar, R, R¹, R^(a), R⁶ and R⁷, are independently selected from the        group consisting of halogen, (C₁-C₆)alkyl, (C₁-C₆)alkoxy, —NO₂,        —C≡N, —CO₂R⁵, —C(═O)O(C₁-C₃)alkyl, —OH, —(C₂-C₆)—OH,        phosphonato, —NR⁴ ₂, —NHC(═O)(C₁-C₆)alkyl, sulfamyl, carbamyl,        —OC(═O)(C₁-C₃)alkyl, —O(C₂-C₆)—N((C₁-C₆)alkyl)₂ and —CF₃;    -   provided        -   (1) when R¹ is a monovalent peptidyl moiety of molecular            weight less than 1000 and V is —C(═O)—, —C(═S, —S(═O)— or            —SO₂—, and b is 0;        -   then said peptidyl moiety is coupled to M through the            peptide's amino terminus or through a sidechain amino group            to form an amide, thioamide, sulfinamide or sulfonamide            respectively;        -   (2) when R¹ is a monovalent peptidyl moiety of molecular            weight less than 1000 and V is —C(═O)NR³—, —SO₂NR³—, or            —NR⁴—, and b is 0,        -   then said peptidyl moiety is coupled to M through the            peptide's carboxy terminus or through a sidechain carboxyl            group to form an imide, sulfonimide, or carboxamide            respectively; and        -   (3) when R¹ is a monovalent peptidyl moiety of molecular            weight less than 1000 and W is —S— or —O—, and d is 0,        -   then said peptidyl moiety is coupled to M through the            peptide's carboxy terminus or through a sidechain carboxyl            group to form a carbothioic acid ester or the carboxylic            ester respectively;    -   or a salt of such a compound.

Preferred compounds of formula I include, for example, the followingcompounds and salts of such compounds:

-   (E)-2,4,6-trimethoxystyryl-N-[(3-trifluoroacetamido)-4-methoxy-phenyl]-sulfonamide;    and-   (E)-2,4,6-trimethoxystyryl-N-[(3-acetoxyacetamido)-4-methoxyphenyl]-sulfonamide.

According to one embodiment of the invention;

-   -   each V is independently selected from the group consisting of        C(═O), —C(═S)—, —S(═O)—, —SO₂—, —C(═O)NR⁴—, —C(═S)NR⁴— and        —SO₂NR⁴—;    -   wherein the absolute stereochemistry of -Z- is either 1) or L;    -   each R¹ is independently selected from the group consisting of        —H, unsubstituted aryl, substituted aryl, substituted        heterocyclic, unsubstituted heterocyclic, —CO₂R⁵, —C(═O)NR⁴ ₂,        —CHR⁶R⁷, —C(═NH)—NR⁴ ₂ and a monovalent peptidyl moiety with a        molecular weight of less than 1000; provided that when y is 0        and R¹ is —CO₂R⁵, R¹ is not-H; and    -   each R⁶ is independently selected from the group consisting of        —H, —(C₁-C₆)alkyl, —CO₂R⁵, —C(═O)R⁷, —OH, —SR⁴, —(C₁-C₃)alkoxy,        —(C₁-C₃)alkylthio, guanidino, —NR⁴ ₂, phenyl, substituted        phenyl, heterocyclic, substituted heterocyclic and halogen.

According to a preferred sub-embodiment thereof, there are providedcompounds of formula I, wherein Z has an L absolute configuration.

According to a sub-embodiment thereof, there are provided compounds offormula I, wherein R is —H or (C₁-C₆)alkyl.

In a further sub-embodiment, novel compounds of formula I are providedwherein Ar is optionally substituted phenyl.

According to first embodiment of compounds of formula I, there areprovided compounds of the formula III, below:

-   -   Ar is selected from the group consisting of substituted and        unsubstituted aryl, and substituted and unsubstituted        heteroaryl;    -   X¹ is selected from the group consisting of (i), (ii) and (iii)        below:    -   wherein X¹ is optionally protected with one or more chemical        protecting groups;    -   g is 0 or 1;    -   M is a bivalent connecting group selected from the group        consisting of —(C₁-C₆)alkylene-, —(CH₂)_(a)—V—(CH₂)_(b)—,        —(CH₂)_(d)—W—(CH₂)_(e) and -Z-;    -   y is selected from the group consisting of 0 and 1;    -   V is selected from the group consisting of —C(═O)—, —C(═S)—,        —S(═O)—, —SO₂—, —C(═O)NR⁴—, —C(═S)NR⁴— and —SO₂NR⁴—    -   W is selected from the group consisting of —NR⁴—, —O— and —S—;    -   a is selected from the group consisting of 0, 1, 2 and 3;    -   b is selected from the group consisting of 0, 1, 2 and 3;    -   d is selected from the group consisting of 1, 2 and 3;    -   e is selected from the group consisting of 0, 1, 2 and 3;    -   wherein the absolute stereochemistry of -Z- is either D or L;    -   R is selected from the group consisting of —H, (C₁-C₆)alkyl,        (C₁-C₆)alkoxy, (C₃-C₆)alkenyl, (C₂-C₆)heteroalkyl,        (C₃-C₆)heteroalkenyl, (C₂-C₆)hydroxyalkyl, substituted aryl,        unsubstituted aryl, substituted heterocyclic, unsubstituted        heterocyclic, substituted aryl(C₁-C₃)alkyl, unsubstituted        aryl(C₁-C₃)alkyl, substituted heterocyclic(C₁-C₃)alkyl and        unsubstituted heterocyclic(C₁-C₃)alkyl;    -   R^(a) is selected from the group consisting of —H, —CH₃,        —(CH₂)₃—NH—C(NH₂)(═NH), —CH₂C(═O)NH₂, —CH₂COOH, —CH₂SH,        —(CH₂)₂C(═O)—NH₂, —(CH₂)₂COOH, —CH₂-(2-imidazolyl),        —CH(CH₃)—CH₂—CH₃, —CH₂CH(CH₃)₂, —(CH₂)₄—NH₂, —(CH₂—S—CH₃,        phenyl, CH₂-phenyl, —CH₂—OH, —CH(OH)—CH₃, —CH₂—(3-indolyl),        —CH₂-(4-hydroxyphenyl), —CH(CH₃)₂ and —CH₂—CH₃; and includes        compounds wherein R^(a) and R¹ combine to form a 5-, 6- or        7-membered heterocyclic ring;    -   R¹ is selected from the group consisting of —H, unsubstituted        aryl, substituted aryl, substituted heterocyclic, unsubstituted        heterocyclic, —CO₂R⁵, —C(═O)NR⁴ ₂, —CHR⁶R⁷, —C(═NH)—NR⁴ ₂ and a        monovalent peptidyl moiety with a molecular weight of less than        1000; provided that when y is 0 and R¹ is —CO₂R⁵, R⁵ is not —H;    -   each R² is independently selected from the group consisting of        —H, —(C₁-C₆)alkyl, and aryl(C₁-C₃)alkyl, wherein —R² and M-R¹        may optionally be linked covalently to form a 5-, 6- or        7-membered substituted or unsubstituted heterocycle;    -   R³ is independently selected from —(C₁-C₆)alkyl;    -   each R⁴ is independently selected from the group consisting of        —H, and —(C₁-C₆)alkyl;    -   wherein:    -   when R⁴ and R¹ are bonded to the same nitrogen atom, R¹ and R⁴        may combine to form a heterocycle; and    -   when two R⁴ groups are geminally bonded to the same nitrogen,        the two R⁴ groups may combine to form a heterocycle;    -   each R⁵ is independently selected from the group consisting of        —H, —(C₁-C₆)alkyl and —(C₁-C₆)acyl;    -   R⁶ is selected from the group consisting of —H, —(C₁-C₆)alkyl,        —CO₂R⁵, —C(═O)R⁷, —OH, —SR⁴, —(C₁-C₃)alkoxy, —(C₁-C₃)alkylthio,        guanidino, —NR⁴ ₂, phenyl, substituted phenyl, heterocyclic,        substituted heterocyclic and halogen;    -   R⁷ is selected from the group consisting of —H, halogen,        —(C₁-C₆)alkyl, —NR⁴ ₂ and heterocycles containing two nitrogen        atoms; and    -   wherein the substituents for the substituted aryl and        substituted heterocyclic groups comprising or included within        Ar, R, R¹, R¹, R^(a), R⁶ and R⁷, are independently selected from        the group consisting of halogen, (C₁-C₆)alkyl, (C₁-C₆)alkoxy,        —NO₂, —C≡N, —CO₂R⁵, —C(═O)O(C₁-C₃)allyl, —OH, —(C₂-C₆)—OH,        phosphonato, —NR⁴ ₂, —NHC(═O)(C₁-C₆)alkyl, sulfamyl, carbamyl,        —OC(═O)(C₁-C₃)alkyl, —O(C₂-C₆)—N((C₁-C₆)alkyl), and —CF₃;    -   provided    -   (1) when R¹ is a monovalent peptidyl moiety of molecular weight        less than 1000 and V is —C(═O), —C(═S), —S(═O) or SO₂—, and b is        0;    -   then said peptidyl moiety is coupled to M through the peptide's        amino terminus or through a sidechain amino group to form an        amide, thioamide, sulfinamide or sulfonamide respectively;    -   (2) when R¹ is a monovalent peptidyl moiety of molecular weight        less than 1000 and V is —C(═O)NR³—, —SO₂NR³—, or —NR⁴—, and b is        0,    -   then said peptidyl moiety is coupled to M through the peptide's        carboxy terminus or through a sidechain carboxyl group to form        an imide, sulfonimide, or carboxamide respectively; and    -   (3) when R¹ is a monovalent peptidyl moiety of molecular weight        less than 1000 and W is —S— or —O—, and d is 0,    -   then said peptidyl moiety is coupled to M through the peptide's        carboxy terminus or through a sidechain carboxyl group to form a        carbothioic acid ester or the carboxylic ester respectively;    -   or a salt of such a compound.

Suitable protecting groups are those groups which are stable toreactions designed to derivatize the 3-amino group of formula III.Subsequently said protecting groups are optionally removed to regeneratethe group X¹.

In another sub-embodiment, thereof, there are provided compounds of theformula IIIa, below:

wherein:

-   -   Ar is selected from the group consisting of substituted and        unsubstituted aryl, and substituted and unsubstituted        heteroaryl;    -   X² is selected from the group consisting of NO₂ and —NH₂,        optionally protected with a chemical protecting group;    -   g is 0 or 1;    -   R is selected from the group consisting of —H, (C₁-C₆)alkyl,        (C₁-C₆)alkoxy, (C₃-C₆)alkenyl, (C₂-C₆)heteroalkyl,        (C₃-C₆)heteroalkenyl, (C₂-C₆)hydroxyalkyl, substituted aryl,        unsubstituted aryl, substituted heterocyclic, unsubstituted        heterocyclic, substituted aryl(C₁-C₃)alkyl, unsubstituted        aryl(C₁-C₃)alkyl, substituted heterocyclic(C₁-C₃)alkyl and        unsubstituted heterocyclic(C₁-C₃)alkyl;    -   R² is independently selected from the group consisting of —H,        —(C₁-C₆)alkyl, and aryl(C₁-C₃)alkyl, wherein —R² and M)_(y)-R¹        may optionally be linked covalently to form a 5-, 6- or        7-membered substituted or unsubstituted heterocycle;    -   each R³ is independently selected from —(C₁-C₆)alkyl;    -   or a salt of such a compound.

In a sub-embodiment thereof, there is provided a compound wherein Ar isoptionally substituted phenyl; or a salt of such a compound.

According to another sub-embodiment of compounds of formula I, there isprovided compounds of formula I′:

wherein:

-   -   X is selected from the group consisting of (i) and (ii) below:    -   X¹ is selected from the group consisting of (i), (ii) and (iii)        below:        wherein X¹ is optionally protected with one or more chemical        protecting groups;    -   g is 0 or 1;    -   each M is a bivalent connecting group independently selected        from the group consisting of C₁-C₆)alkylene-,        —(CH₂)_(a)—V—(CH₂)_(b)—, —(CH₂)_(d)—W—(CH₂)_(e)— and -Z-;    -   each y is independently selected from the group consisting of 0        and 1;    -   each V is independently selected from the group consisting of        C(═O), —C(═S), —S(═O), —SO₂—, —C(═O)NR⁴—, —C(═S)NR⁴— and        —SO₂NR⁴—,    -   each W is independently selected from the group consisting of        —NR⁴—, —O— and —S—;    -   each a is independently selected from the group consisting of 0,        1, 2 and 3;    -   each b is independently selected from the group consisting of 0,        1, 2 and 3;    -   each d is independently selected from the group consisting of 1,        2 and 3;    -   each e is independently selected from the group consisting of 0,        1, 2 and 3;    -   wherein the absolute stereochemistry of -Z- is either D or L;    -   R is selected from the group consisting of —H, (C₁-C₆)alkyl,        (C₁-C₆)alkoxy, (C₃-C₆)alkenyl, (C₂-C₆)heteroalkyl,        (C₃-C₆)heteroalkenyl, (C₂-C₆)hydroxyalkyl, substituted aryl,        unsubstituted aryl, substituted heterocyclic, unsubstituted        heterocyclic, substituted aryl(C₁-C₃)alkyl, unsubstituted        aryl(C₁-C₃)alkyl, substituted heterocyclic(C₁-C₃)alkyl and        unsubstituted heterocyclic(C₁-C₃)alkyl;    -   each R^(a) is independently selected from the group consisting        of —H, —CH₃, —(CH₂)₃—NH—C(NH₂)(—NH), —CH₂C(═O)NH₂, —CH₂COOH,        —CH₂SH, —(CH₂)₂C(═O)—NH₂, —(CH₂)₂COOH, —CH₂-(2-imidazolyl),        —CH(CH₃)—CH₂—CH₃, —CH₂CH(CH₃)₂, —(CH₂)₄—NH₂, —(CH₂), —S—CH₃,        phenyl, CH₂-phenyl, —CH₂—OH, —CH(OH)—CH₃, —CH₂-(3-indolyl),        —CH₂-(4-hydroxyphenyl), —CH(CH₃)₂ and —CH₂—CH₃; and includes        compounds wherein R^(a) and R¹ combine to form a 5-, 6- or        7-membered heterocyclic ring;    -   each R¹ is independently selected from the group consisting of        —H, unsubstituted aryl, substituted aryl, substituted        heterocyclic, unsubstituted heterocyclic, —CO₂R⁵, —C(═O)NR⁴ ₂,        —CHR⁶R⁷, —C(═NH)—NR⁴ ₂ and a monovalent peptidyl moiety with a        molecular weight of less than 1000; provided that when y is 0        and R¹ is —CO₂R⁵, R⁵ is not —H;    -   each R² is independently selected from the group consisting of        —H, —(C₁-C₆)alkyl, and aryl(C₁-C₃)alkyl, wherein —R² and        -(M)_(y)-R¹ may optionally be linked covalently to form a 5-, 6-        or 7-membered substituted or unsubstituted heterocycle;    -   each R³ is independently selected from —(C₁-C₆)alkyl;    -   each R⁴ is independently selected from the group consisting of        —H, and —(C₁-C₆)alkyl;    -   wherein:    -   when R⁴ and R¹ are bonded to the same nitrogen atom, R¹ and R⁴        may combine to form a heterocycle; and    -   when two R⁴ groups are geminally bonded to the same nitrogen,        the two R⁴ groups may combine to form a heterocycle;    -   each R⁵ is independently selected from the group consisting of        —H, —(C₁-C₆)alkyl and —(C₁-C₆)acyl;    -   each R⁶ is independently selected from the group consisting of        —H, —(C₁-C₆)alkyl, —CO₂R⁵, —C(═O)R⁷, —OH, —SR⁴, —(C₁-C₃)alkoxy,        —(C₁-C₃)alkylthio, guanidino, —NR², phenyl, substituted phenyl,        heterocyclic, substituted heterocyclic and halogen;    -   each R⁷ is independently selected from the group consisting of        —H, halogen, —(C₁-C₆)alkyl, —NR⁴ ₂ and heterocycles containing        two nitrogen atoms; and    -   Q is selected from the group consisting of —H, —(C₁-C₆)alkoxy,        halogen, —(C₁-C₆)alkyl and —NR⁴ ₂;    -   wherein the substituents for the substituted aryl and        substituted heterocyclic groups comprising or included within R,        R¹, R^(a), R⁶ and R⁷, are independently selected from the group        consisting of halogen, (C₁-C₆)alkyl, (C₁-C₆)alkoxy, —NO₂, —C≡N,        —CO₂R⁵, —C(═O)O(C₁-C₃)alkyl, —OH, —(C₂-C₆)—OH, phosphonato, —NR⁴        ₂, —NHC(═O)(C₁-C₆)alkyl, sulfamyl, carbamyl,        —OC(═O)(C₁-C₃)alkyl, —O(C₂-C₆)—N((C₁-C₆)allyl)₂ and —CF₃;    -   provided    -   (1) when R¹ is a monovalent peptidyl moiety of molecular weight        less than 1000 and V is —C(═O)—, —C(═S)—, —S(═O)— or —SO₂—, and        b is 0;    -   then said peptidyl moiety is coupled to M through the peptide's        amino terminus or through a sidechain amino group to form an        amide, thioamide, sulfinamide or sulfonamide respectively;    -   (2) when R¹ is a monovalent peptidyl moiety of molecular weight        less than 1000 and V is C(═O)NR³—, —SO₂NR³—, or —NR⁴—, and b is        0,    -   then said peptidyl moiety is coupled to M through the peptide's        carboxy terminus or through a sidechain carboxyl group to form        an imide, sulfonimide, or carboxamide respectively; and    -   (3) when R¹ is a monovalent peptidyl moiety of molecular weight        less than 1000 and W is —S— or —O—, and d is 0,    -   then said peptidyl moiety is coupled to M through the peptide's        carboxy terminus or through a sidechain carboxyl group to form a        carbothioic acid ester or the carboxylic ester respectively;    -   or a salt of such a compound.

In a further sub-embodiment there are provided compounds of formulaIIIa′:

wherein:

-   -   X² is selected from the group consisting of NO₂ and —NH₂,        optionally protected with a chemical protecting group;    -   g is 0 or 1;    -   R is selected from the group consisting of —H, (C₁-C₆)alkyl,        (C₁-C₆)alkoxy, (C₃-C₆)alkenyl, (C₂-C₆)heteroalkyl,        (C₃-C₆)heteroalkenyl, (C₂-C₆)hydroxyalkyl, substituted aryl,        unsubstituted aryl, substituted heterocyclic, unsubstituted        heterocyclic, substituted aryl(C₁-C₃)alkyl, unsubstituted        aryl(C₁-C₃)alkyl, substituted heterocyclic(C₁-C₃)alkyl and        unsubstituted heterocyclic(C₁-C₃)alkyl;    -   R² is independently selected from the group consisting of —H,        —(C₁-C₆)alkyl, and aryl(C₁-C₃)alkyl, wherein —R² and (M)_(y)—R        may optionally be linked covalently to form a 5-, 6- or        7-membered substituted or unsubstituted heterocycle;    -   each R³ is independently selected from —(C₁-C₆)alkyl;    -   each R⁴ is independently selected from the group consisting of        —H, and —(C₁-C₆)alkyl;    -   Q is selected from the group consisting of —H, —(C₁-C₆)alkoxy,        halogen, —(C₁-C₆)alkyl and —NR⁴ ₂;    -   or a salt of such a compound.

The strategy for synthesizing compounds of formula I involvesderivatization of primary or secondary amino group at the 3-position ofan intermediate of formula IIIa′. Such derivatizations of the 3-aminogroup include for example reactions to form carboxamides, sulfonamidesalkyl amines, nitrogen-containing heterocycles, imines, guanidines,ureas, amidines, and amino ketones.

The intermediate of formula IIIa′ also incorporates an optional group atthe 5-position, which can be a nitro group or a protected amino group.In the synthetic strategy, this 5-substituent serves as a second, latentamino group. The use of this protecting group strategy allows fordifferential derivatization of these two amino groups, i.e., the 3-aminogroup of formula IIIa′ and the moiety at the 5-position which is inertto the conditions of the derivatization of the 3-amino group. Hence, thesynthetic route involves first derivatizing the 3-amino group, followedby conversion of the 5-substituent to an amino group via either (a)deprotection, if X² is a protected amine, or (b) chemical reduction ifX² is a nitro group. From a retrosynthetic viewpoint, this syntheticroute allows for differential derivatization of two amino groups, one atthe 5-position which is protected (either with a chemical protectinggroup, or by being in a nitro oxidation state) and thereby inert to theconditions of the derivatization of the 3-amino group. Suitable chemicalprotecting groups for the 5-position protected amine, include forexample, benzyl, 2,4-dimethoxy-benzyl and benzyloxycarbonyl (CBZ). In asimilar manner, when X² is —NO₂, the 3-amino group may be derivatized inthe aforesaid manner. Subsequently the —NO₂ group may optionally bechemically reduced to the corresponding 5-amino group via a variety ofprocedures known to those skilled in the art.

Subsequently, the 5-amino group, generated by either reduction of a5-nitro group or by removing a protecting group from a protected 5-aminocompound, is optionally derivatized. Derivatization of the 5-amino groupmay be the same or different from the derivatization of the 3-aminogroup.

According to a sub-embodiment of said compounds of formula IIIa′,compounds are provided wherein Q is (C₁-C₆)alkoxy; or salts thereof.

According to another sub-embodiment compounds of formula IIIa′ areprovided wherein Q is —OCH₃; or salts thereof.

According to a further sub-embodiment, compounds of formula IIIa′ areprovided wherein R³ is —CH₃; or salts thereof.

One such compound is(E)-2,4,6-trimethoxystyryl-4-methoxy-3-aminophenylsulfonamide, or a saltof such a compound.

According to a second embodiment of the invention of formula I,

-   -   X is    -   and y is 1; M is —(CH₂)_(a)—V—(CH₂)_(b)—; and V is —C(═O)—.

According to a sub-embodiment thereof are provided compounds wherein Aris optionally substituted phenyl; and salts thereof.

According to a sub-embodiment thereof, compounds of the formula IV,below, and salts thereof are provided:

In a sub-embodiment thereof, compounds of formula IV are providedwherein g is 0; and salts thereof.

Preferred compounds of formula IV, include, for example, the followingcompounds and salts thereof:

-   (E)-2,4,6-trimethoxystyryl-N-(3-carboxyacetamido-4-methoxyphenyl)sulfonamide;-   (E)-2,4,6-trimethoxystyryl-N-[3-(3,5,dinitrobenzamido)₄-methoxy-phenyl]-sulfonamide;-   (E)-2,4,6-trimethoxystyryl-N-[3-(3,5,diaminobenzamido)-4-methoxy-phenyl]-sulfonamide;-   (E)-2,4,6-trimethoxystyryl-N-(3-chloroacetamido-4-methoxyphenyl)-sulfonamide;-   (E)-2,4,6-trimethoxystyryl-N-[3-(4-methylpiperazinyl)acetamide;-   methoxyphenyl]sulfonamide;-   (E)-2,4,6-trimethoxystyryl-N-[(3-benzamido)-4-methoxyphenyl]-sulfonamide;-   (E)-2,4,6-trimethoxystyryl-N-3    [(4-nitrobenzamido)-4-methoxyphenyl]-sulfonamide;-   (E)-2,4,6-trimethoxystyryl-N-3    [(4-aminobenzamido)-4-methoxyphenyl]-sulfonamide;-   (E)-2,4,6-trimethoxystyryl-N-[(3-acetamido)-4-methoxyphenyl]-sulfonamide;-   (E)-2,4,6-trimethoxystyryl-N-[(3-hydroxyacetamido)-4-methoxyphenyl)]sulfonamide;    and-   (E)-2,4,6-trimethoxystyryl-N-[(3-N,N-dimethylacetamido)-4-methoxyphenyl]-sulfonamide.

According to a third embodiment of the invention of formula I, X is

-   -   and y is 1; and M is -Z-.

According to a sub-embodiment thereof, compounds are provided wherein Aris optionally substituted phenyl, and salts thereof.

According to another sub-embodiment thereof, compounds of formula V andsalts thereof, are provided:

wherein:

-   -   each R^(a) is independently selected from the group consisting        of —H, —CH₃, —(CH₂)₃—NH—C(H₂)(NH, —CH₂C(═O)NH₂, —CH₂COOH,        —CH₂SH, —(CH₂)₂C(═O)—NH₂, —(CH₂)COOH, —CH₂-(2-imidazolyl),        —CH(CH₃)—CH₂—CH₃, —CH₂CH(CH₃)₂, —(CH₂)₄—NH₂, —(CH₂)₂—S—CH₃,        phenyl, CH₂-phenyl, —CH₂—OH, —CH(OH)—CH₃, —CH₂-(3-indolyl),        —CH₂-(4-hydroxyphenyl), —CH(CH₃)₂ and —CH₂CH₃, and includes        compounds wherein R^(a) and R¹ combine to form a 5-, 6- or        7-membered heterocyclic ring.

Heterocyclic rings formed by the combination of R^(a) and R¹ include forexample: pyrrolidine, hydroxy pyrrolidine, piperidine, homopiperidineand thiazolidine.

In a sub-embodiment thereof, compounds of formula V are provided whereing is 0; and salts thereof.

Preferred compounds of formula V include, for example, the followingcompounds and salts thereof:

-   (E)-2,4,6-trimethoxystyryl-N-(3-amino-4-methoxyphenyl)sulfonamide-L-lysineamide;-   (E)-2,4,6-trimethoxystyryl-N-(3-amino-4-methoxyphenyl)sulfonamide-L-serineamide;    and-   (E)-2,4,6-trimethoxystyryl-N-(3-amino-4-methoxyphenyl)sulfonamide-D-serineamide;

According to a fourth embodiment of the invention of formula I,

-   -   X is    -   and y is 1; M is —(CH₂)_(a)—V—(CH₂)_(b)—; and V is —SO₂—.

According to a further sub-embodiment thereof compounds are providedwherein Ar is optionally substituted phenyl; and salts thereof.According to a sub-embodiment thereof compounds of formula VI and saltsthereof are provided:

In one such embodiment, compounds of formula VI are provided wherein gis 0; and salts thereof.

Compounds of formula VI, include for example the following compounds andsalts thereof:

-   (E)-2,4,6-trimethoxystyryl-N-(3-carboxymethylsulfamyl-4-methoxyphenyl)-sulfonamide;-   (E)-2,4,6-trimethoxystyryl-N-[3-(3,5-dinitrobenzenesulfamyl)-4-methoxy-phenyl]sulfonamide;    and-   (E)-2,4,6-trimethoxystyryl-N-[3-(3,5-diaminobenzenesulfamyl)-4-methoxy    phenyl]sulfonamide.

According to a fifth embodiment of the invention of formula I, X is

-   -   and y is 0 and R¹ is —C(═NH)—NR⁴ ₂.

According to a sub-embodiment thereof compounds are provided wherein Aris optionally substituted phenyl; and salts thereof. According toanother sub-embodiment thereof, compounds of formula VII, and saltsthereof, are provided:

In a sub-embodiment thereof, compounds of formula VII are providedwherein g is 0; and salts thereof.

One such compound is(E)-2,4,6-trimethoxystyryl-N-3-guanidino-4-methoxy-phenyl)sulfonamide,or a salt of such a compound.

According to a sixth embodiment of the invention of formula I, X is

-   -   and y is 1; and M is —(C₁-C₆)alkylene-.

According to one sub-embodiment thereof, compounds are provided whereinAr is optionally substituted phenyl; and salts thereof.

According to another sub-embodiment thereof, compounds of the formulaVIII, and salts thereof, are provided:

In a sub-embodiment thereof, compounds of formula VIII are providedwherein g is 0; and salts thereof.

Exemplary compounds of formula VIII include for example, the followingcompounds and salts thereof:

-   (E)-2,4,6-trimethoxystyryl-N-(3-carboxymethylamino-4-methoxy-phenyl)sulfonamide;    and-   (E)-2,4,6-trimethoxystyryl-N-(3-N-methylamino-4-methoxyphenyl)-sulfonamide.

According to a seventh embodiment of the invention, compounds of theformula IX and salts thereof are provided:

In a sub-embodiment thereof, compounds of formula IX are providedwherein g is 0; and salts thereof.

One such compound is(E)-2,4,6-trimethoxystyryl-N-3[(4-nitrophenylimino)-4-methoxyphenyl]sulfonamide,or a salt of such a compound.

According to an eighth embodiment of the invention of formula I,

-   -   X is    -   and y is 1; M is —(CH₂)_(a)—V—(CH₂)_(b)—; and V is C(═O)NR⁴—.

According to one sub-embodiment thereof compounds are provided whereinAr is optionally substituted phenyl; and salts thereof.

According to another sub-embodiment thereof, compounds of formula X andsalts thereof are provided:

In a sub-embodiment thereof, compounds of formula X are provided whereing is 0; and salts thereof.

An exemplary compound of formula X is(E)-2,4,6-trimethoxystyryl-N-(3-ureido-4-methoxyphenyl)sulfonamide, or asalt of such a compound.

According to a ninth embodiment of the invention, compounds of theformula II and salts thereof are provided:

wherein:

-   -   Ar is selected from the group consisting of substituted and        unsubstituted aryl, and substituted and unsubstituted        heteroaryl;    -   X¹ is selected from the group consisting of (i), (ii) and (iii)        below:    -   wherein X¹ is optionally protected with one or more chemical        protecting groups;    -   g is 0 or 1;    -   M is a bivalent connecting group selected from the group        consisting of —(C₁-C₆)alkylene-, —(CH₂)_(a)—V—(CH₂)_(b)—,        —(CH₂)_(d)—W—(CH₂)_(e)— and -Z-;    -   y is selected from the group consisting of 0 and 1;    -   V is selected from the group consisting of —C(═O)—, —C(═S)—,        —S(═O), —SO₂—, —C(═O)NR⁴—, —C(═S)NR⁴— and O₂NR⁴—    -   W is selected from the group consisting of —NR⁴—, —O— and —S—;    -   a is selected from the group consisting of 0, 1, 2 and 3;    -   b is selected from the group consisting of 0, 1, 2 and 3;    -   d is selected from the group consisting of 1, 2 and 3;    -   e is selected from the group consisting of 0, 1, 2 and 3;    -   wherein the absolute stereochemistry of -Z- is either D or L;    -   R is selected from the group consisting of —H, (C₁-C₆)alkyl,        (C₁-C₆)alkoxy, (C₃-C₆)alkenyl, (C₂-C₆)heteroalkyl,        (C₃-C₆)heteroalkenyl, (C₂-C₆)hydroxyalkyl, substituted aryl,        unsubstituted aryl, substituted heterocyclic, unsubstituted        heterocyclic, substituted aryl(C₁-C₃)alkyl, unsubstituted        aryl(C₁-C₃)alkyl, substituted heterocyclic(C₁-C₃)alkyl and        unsubstituted heterocyclic(C₁-C₃)alkyl;    -   R^(a) is selected from the group consisting of —H, —CH₃,        —(CH₂)₃—NH—C(NH₂)(═NH), —CH₂C(═O)NH₂, —CH₂COOH, —CH₂SH,        —(CH₂)₂C(═O)—NH₂, CH₂₂COOH, —CH₂-(2-imidazolyl),        —CH(CH₃)—CH₂—CH₃, —CH₂CH(CH₃, —(CH₂)₄—NH₂, —(CH₂₂—S—CH₃, phenyl,        CH₂-phenyl, —CH₂—OH, —CH(OH)—CH₃, —CH₂-(3-indolyl),        —CH₂-(4-hydroxyphenyl), —CH(CH₃)₂ and —CH₂—CH₃; and includes        compounds wherein R¹ and R¹ combine to form a 5-, 6- or        7-membered heterocyclic ring;    -   R¹ is selected from the group consisting of —H, unsubstituted        aryl, substituted aryl, substituted heterocyclic, unsubstituted        heterocyclic, —CO₂R⁵, —C(═O)NR⁴ ₂, —CHR⁶R⁷, —C(═NH)—NR⁴ ₂ and a        monovalent peptidyl moiety with a molecular weight of less than        1000; provided that when y is 0 and R¹ is —CO₂R⁵, R¹ is not —H;    -   each R² is independently selected from the group consisting of        —H, —(C₁-C₆)alkyl, and aryl(C₁-C₃)alkyl, wherein —R² and        -(M)_(y)-R¹ may optionally be linked covalently to form a 5-, 6-        or 7-membered substituted or unsubstituted heterocycle;    -   R³ is independently selected from —(C₁-C₆)alkyl;    -   each R⁴ is independently selected from the group consisting of        —H, and —(C₁-C₆)alkyl;    -   wherein:    -   when R⁴ and R¹ are bonded to the same nitrogen atom, R¹ and R⁴        may combine to form a heterocycle; and    -   when two R⁴ groups are geminally bonded to the same nitrogen,        the two R⁴ groups may combine to form a heterocycle;    -   each R⁵ is independently selected from the group consisting of        —H, —(C₁-C₆)alkyl and —(C₁-C₆)acyl;    -   R⁶ is selected from the group consisting of —H, —(C₁-C₆)alkyl,        —CO₂R⁵, —C(═O)R⁷, —OH, —SR⁴, —(C₁-C₃)alkoxy, —(C₁-C₃)alkylthio,        guanidino, —NR⁴ ₂, phenyl, substituted phenyl, heterocyclic,        substituted heterocyclic and halogen;    -   R⁷ is selected from the group consisting of —H, halogen,        —(C₁-C₆)alkyl, —NR⁴ ₂ and heterocycles containing two nitrogen        atoms; and    -   wherein the substituents for the substituted aryl and        substituted heterocyclic groups comprising or included within        Ar, R, R¹, R², R^(a), R⁶ and R⁷, are independently selected from        the group consisting of halogen, (C₁-C₆)alkyl, (C₁-C₆)alkoxy,        —NO₂, —C—N, —CO₂R⁵, —C(═O)O(C₁-C₃)alkyl, —OH, —(C₂-C₆)—OH,        phosphonato, —NR⁴ ₂, —NHC(═O)(C₁-C₆)alkyl, sulfamyl, carbamyl,        —OC(═O)(C₁-C₃)alkyl, —O(C₂-C₆)—N((C₁-C₆)alkyl)₂ and —CF₃;    -   provided    -   (1) when R¹ is a monovalent peptidyl moiety of molecular weight        less than 1000 and V is —C(═O)—, —C(═S), —S(═O) or —SO₂—, and b        is 0;    -   then said peptidyl moiety is coupled to M through the peptide's        amino terminus or through a sidechain amino group to form an        amide, thioamide, sulfinamide or sulfonamide respectively;    -   (2) when R¹ is a monovalent peptidyl moiety of molecular weight        less than 1000 and V is —C(═O)N³—, —SO₂NR³—, or —NR⁴—, and b is        0,    -   then said peptidyl moiety is coupled to M through the peptide's        carboxy terminus or through a sidechain carboxyl group to form        an imide, sulfonimide, or carboxamide respectively; and    -   (3) when R¹ is a monovalent peptidyl moiety of molecular weight        less than 1000 and W is —S— or —O—, and d is 0,    -   then said peptidyl moiety is coupled to M through the peptide's        carboxy terminus or through a sidechain carboxyl group to form a        carbothioic acid ester or the carboxylic ester respectively;    -   or a salt of such a compound.

According to a sub-embodiment thereof, compounds of formula Iia areprovided:

wherein:

-   -   g is 0 or 1;    -   R is selected from the group consisting of —H, (C₁-C₆)alkyl,        (C₁-C₆)alkoxy, (C₃-C₆)alkenyl, (C₂-C₆)heteroalkyl,        (C₃-C₆)heteroalkenyl, (C₂-C₆)hydroxyalkyl, substituted aryl,        unsubstituted aryl, substituted heterocyclic, unsubstituted        heterocyclic, substituted aryl(C₁-C₃)alkyl, unsubstituted        aryl(C₁-C₃)alkyl, substituted heterocyclic(C₁-C₃)alkyl and        unsubstituted heterocyclic(C₁-C₃)alkyl;    -   R³ is independently selected from C₁-C₆)alkyl;    -   X² is selected from the group consisting of NO₂ and —NH₂,        optionally protected with a chemical protecting group;    -   or a salt of such a compound.

Compounds of formula Ha are intermediates in the synthesis of compoundsof formula I wherein the 3-nitro group may be chemically reduced withfor example, hydrazine and a palladium catalyst to form a compound offormula IIIa as described above.

One such compound of formula IIa is(E)-2,4,6-trimethoxystyryl-4-methoxy-3-nitrophenylsulfonamide.

In another embodiment, an intermediate in the preparation of compoundsof the present invention is a compound of the formula C or a salt ofsuch a compound:

In a further embodiment, an intermediate in the preparation of compoundsof the present invention is a compound of the formula C′; or a salt ofsuch a compound.

In each of the formulas C and C′:

R³ is independently selected from —(C₁-C₆)alkyl;

-   -   X² is selected from the group consisting of NO₂ and —NH₂,        optionally protected with a chemical protecting group; and g is        0 or 1.

According to other embodiments of the invention, processes for preparingcompounds according to formula I are provided.

In one such embodiment, a process for preparing a compound of formula Iis provided comprising:

-   -   (1) coupling a compound of formula IIIa or a salt of such a        compound:        wherein:    -   Ar is selected from the group consisting of substituted and        unsubstituted aryl, and substituted and unsubstituted        heteroaryl;    -   X² is selected from the group consisting of NO₂ and —NH₂,        optionally protected with a chemical protecting group;    -   g is 0 or 1;    -   R is selected from the group consisting of —H, (C₁-C₆)alkyl,        (C₁-C₆)alkoxy, (C₃-C₆)alkenyl, (C₂-C₆)heteroalkyl,        (C₃-C₆)heteroalkenyl, (C₂-C₆)hydroxyalkyl, substituted aryl,        unsubstituted aryl, substituted heterocyclic, unsubstituted        heterocyclic, substituted aryl(C₁-C₃)alkyl, unsubstituted        aryl(C₁-C₃)alkyl, substituted heterocyclic(C₁-C₃)alkyl and        unsubstituted heterocyclic(C₁-C₃)alkyl;    -   each R³ is independently selected from —(C₁-C₆)alkyl;    -   or a salt of such a compound.        with a compound of formula XI:        R¹-A  XI    -   wherein one or more functional groups comprising R¹ are        optionally protected by chemical protecting groups; and    -   wherein A is a moiety containing an electrophilic reactive        center, and said moiety is selected from the group consisting        of:        -   (a) an alkyl moiety having a leaving group, e.g., a moiety            such as a halide, a mesylate or a tosylate;        -   (b) an aryl halide moiety or aryl pseudo halide moiety.        -   (c) a carboxylic acid moiety activated with a leaving group,            for example a carboxylic acid chloride moiety or a            carboxylic acid anhydride moiety;        -   (d) a sulfonic acid moiety activated with a leaving group,            for example a sulfonyl chloride moety;        -   (e) a carbamic acid moiety activated with a leaving group,            for example a carbamyl chloride moiety;        -   (f) a cyanate moiety, for example, potassium cyanate;        -   (g) an aldehyde or ketone moiety, or a hydrate thereof, or a            ketal or acetal thereof;        -   (h) a carboxylic acid moiety or an amino acid moiety,            wherein an amide coupling agent is employed in the reaction;            and        -   (i) a moiety that is the product of the reaction of a            substituted thiourea moiety and a 1-methyl- or            1-phenyl-2-halopyridinium salt, preferably            2-chloro-1-methylpyridinium iodide, which iodide is also            known as Mukaima's reagent;            to form a compound of formula Ia:    -   (2) optionally:        -   (a) when —X² is —NH₂ protected with a protecting group,            removing said protecting group from said —X² to yield a            compound of formula Ib; or        -   (b) when —X² is —NO₂, chemically reducing said —NO₂;        -   to form a compound of formula Ib:    -   (3) optionally coupling said compound of formula Ib or a salt of        such a compound:    -   with a compound of formula XI:        R¹-A  XI    -   wherein one or more functional groups comprising R¹ are        optionally protected by chemical protecting groups and A is        defined as above; and    -   (4) optionally removing said protecting groups protecting        functionalities comprising R¹ to form a compound of formula I:    -   or a salt of such a compound.

In the aforesaid process of coupling compounds of formula IIIa tocompounds of formula XI, and the coupling of compounds of formula Ib tocompounds compounds of formula A, the electrophile XI in the secondcoupling may be the same or different from that in the first coupling.Halides which may comprise a leaving group component of theelectrophylic functionality A are preferably chloro, bromo or iodo. Theterm “pseudo halide” refers to a moiety which behaves like a halide inpalladium or nickel-catalyzed amination reactions. Pseudo halidemoieties include for example, triflates and mesylates.

Carboxylic acid moieties which may comprise the electrophilicfunctionality A include, for example, amino acid residues bearingoptional protecting groups on any alpha-amino functionality, sidechainamino functionality, alpha carboxylic acid functionality, sidechaincarboxylic acid functionality or other sidechain functionalities thatrequire a protecting group. Such amino acids may be naturally occurringamino acids or synthetic amino acids including amino acids of either R—or S— absolute configuration.

Additionally, in the aforesaid process of coupling compounds of formulaIIIa to compounds of formula XI, and the coupling of compounds offormula Ib to compounds of formula XI, the term “protecting group”refers to a derivative of a chemical functional group which is employedto derivatize chemical functionalities which would otherwise beincompatable with the conditions of a desired reaction. The protectinggroup renders this functionality stable to the desired reactionconditions and may later be removed to regenerate the de-protectedfunctionality. One example of the use of protecting groups is in thecommon reaction of the amino group of a first amino acid with thecarboxyl group of a second amino acid to form an amide bond. However,since each reactant contains both an amino and a carboxylate functionalgroup, the reaction between them is (1) nonspecific as to which aminogroup will react with which carboxyl group, and (2) subject topolymerization since the product of the reaction still contains bothreactive moieties. A protecting group on the carboxylate of the firstamino acid and a protecting group acid on the amino group of the secondamino acid will serve to limit the reagents to the single desiredreaction of the amino group of the first aminoo acid with the carboxylicacid of the second amino acid and yields a product which will not reactfurther because both of the remaining reactive moieties are blocked byprotecting groups which may be subsequently be removed.

Any chemical functionality that is a structural component of R¹ may beoptionally protected with a chemical protecting group if such aprotecting group is useful in the synthesis of compounds of formula I.Appropriate protecting groups for functionalities comprising R¹, includefor example, such moieties as tert-butoxy carbonyl (t-Boc) or9-fluorenyl-methoxycarbonyl (Fmoc).

Additionally, in the aforesaid process of coupling compounds of formulaIIIa to compounds of formula XI, and the optional coupling of compoundsof formula Ib to compounds of formula XI, “amide coupling reagents” arecompounds used to couple unactivated carboxylic acid moieties to aminogroups, such as the aromatic amino moiety of a compound of formula Iwherein —X is NH₂ (i.e., wherein X is formula (i), y is 0, R¹ is —H andR² is —H). Such amide coupling reagents include for example, reagentssuch as diisopropyl carbodiimide andO-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluoro-phosphate (HATU).

Following the aforesaid process of coupling compounds of formula IIIa tocompounds of formula XI, and the optional coupling of compounds offormula Ib to compounds of formula XI, any protecting groups used in thesynthesis of a compound of formula I, are optionally removed.

According to a further embodiment of the invention, a process forpreparing compounds according to formula IIIa is provided, comprising:

-   -   (1) chemically reducing a compound according to formula IIa:    -   and    -   (2) optionally alkylating the resulting aniline via any suitable        amine alkylation; to form a compound of formula IIIa;        wherein:    -   Ar is selected from the group consisting of substituted and        unsubstituted aryl, and substituted and unsubstituted        heteroaryl;    -   X² is selected from the group consisting of NO₂ and —NH₂,        optionally protected with a chemical protecting group;    -   g is 0 or 1;    -   R is selected from the group consisting of —H, (C₁-C₆)alkyl,        (C₁-C₆)alkoxy, (C₃-C₆)alkenyl, (C₂-C₆)heteroalkyl,        (C₃-C₆)heteroalkenyl, (C₂-C₆)hydroxyalkyl, substituted aryl,        unsubstituted aryl, substituted heterocyclic, unsubstituted        heterocyclic, substituted aryl(C₁-C₃)alkyl, unsubstituted        aryl(C₁-C₃)alkyl, substituted heterocyclic(C—C₃)alkyl and        unsubstituted heterocyclic(C₁-C₃)alkyl;    -   each R³ is independently selected from —(C₁-C₆)alkyl;    -   or a salt of such a compound.

The term “chemically reducing” or “chemical reduction” refers to achemical reaction wherein the reactant which is reduced has a net gainof electrons. In the aforesaid process, the —NO₂ functionality isreduced to a —NH₂ functionality. This reduction reaction may be effectedby a variety of procedures familiar to one of ordinary skill insynthetic chemistry. Such procedures include for example: catalytichydrogenation using a catalyst such as, for example, palladium orplatinum and a hydrogen source, which may be for example, introductionof H₂ gas, or may be via a chemical generator of hydrogen such ashydrazine. Other procedures include for example, metal and metal saltreagents such as, for example, Sn°, Zn°, Fe° and SnCl₂. Other reagentsthat accomplish this type of chemical reduction include for example,sulfite reagents such as sodium hydrosulfite.

Suitable alkylations of an aniline nitrogen include:

-   -   (a) alkylation with an alkyl moiety having a leaving group, such        as, for example and alkyl halide or an alkyl mesylate; and    -   (b) reductive amination, ie., reaction with an aldehyde or a        ketone in the presence of a reducing agent such as sodium cyano        borohydride or sodium triacetoxy borohydride.

Compounds of formula IIa may be prepared by a process comprisingcondensing a compound of formula D

-   -   with a compound of formula E    -   to form a compound of formula IIa:        wherein:    -   Ar is selected from the group consisting of substituted and        unsubstituted aryl, and substituted and unsubstituted        heteroaryl;    -   g is 0 or 1;    -   R³ is independently selected from —(C₁-C₆)alkyl;    -   X² is selected from the group consisting of NO₂ and —NH₂,        optionally protected with a chemical protecting group.

In another embodiment of the invention, a process for preparing acompound of formula I is provided comprising:

-   -   (1) coupling a compound of formula C′:        wherein:    -   X² is —NH₂, optionally protected with a chemical protecting        group.    -   g is 0 or 1;    -   R³ is independently selected from —(C₁-C₆)alkyl;    -   or a salt of such a compound;    -   with a compound of formula XI        R¹-A  XI        wherein:    -   R¹ is selected from the group consisting of —H, unsubstituted        aryl, substituted aryl, substituted heterocyclic, unsubstituted        heterocyclic, —CO₂R⁵, —C(═O)NR⁴ ₂, —CHR⁶R⁷, —C(═N H)—NR⁴² and a        monovalent peptidyl moiety with a molecular weight of less than        1000;    -   each R⁴ is independently selected from the group consisting of        —H, and —(C₁-C₆)alkyl; wherein:    -   when R⁴ and R¹ are bonded to the same nitrogen atom, R¹ and R⁴        may combine to form a heterocycle; and    -   when two R⁴ groups are geminally bonded to the same nitrogen,        the two R⁴ groups may combine to form a heterocycle;    -   each R⁵ is independently selected from the group consisting of        —H, —(C₁-C₆)alkyl and —(C₁-C₆)acyl;    -   R⁶ is selected from the group consisting of —H, —(C₁-C₆)alkyl,        —CO₂R⁵, —C(═O)R⁷, —OH, —SR⁴, —(C₁-C₃)alkoxy, —(C₁-C₃)alkylthio,        guanidino, —NR⁴ ₂, phenyl, substituted phenyl, heterocyclic,        substituted heterocyclic and halogen;    -   R⁷ is selected from the group consisting of —H, halogen,        —(C₁-C₆)alkyl, —NR⁴ ₂ and heterocycles containing two nitrogen        atoms;    -   wherein the substituents for the substituted aryl and        substituted heterocyclic groups comprising or included within        R¹, R⁶ and R⁷, are independently selected from the group        consisting of halogen, (C₁-C₆)alkyl, (C₁-C₆)alkoxy, —NO₂, —C—N,        —CO₂R⁵, —C(═O)O(C₁-C₃)alkyl, —OH, —(C₂-C₆)—OH, phosphonato, —NR⁴        ₂, —NHC(═O)(C₁-C₆)alkyl, sulfamyl, —OC(═O)(C₁-C₃)alkyl,        —O(C₂-C₆)—N((C₁-C₆)alkyl)₂ and —CF₃; and wherein one or more        functional groups comprising R¹ are optionally protected by        chemical protecting groups; and    -   wherein A is a moiety containing an electrophilic reactive        center, said moiety selected from the group consisting of:        -   (a) an alkyl moiety having a leaving group, e.g., a moiety            such as a halide, a mesylate or a tosylate;        -   (b) an aryl halide moiety or aryl pseudo halide moiety.        -   (c) a carboxylic acid moiety activated with a leaving group,            for example a carboxylic acid chloride moiety or a            carboxylic acid anhydride moiety;        -   (d) a sulfonic acid moiety activated with a leaving group,            for example a sulfonyl chloride moety;        -   (e) a carbamic acid moiety activated with a leaving group,            for example a carbamyl chloride moiety;        -   (f) a cyanate moiety, for example, potassium cyanate;        -   (g) an aldehyde or ketone moiety, or a hydrate thereof, or a            ketal or acetal thereof;        -   (h) a carboxylic acid moiety or an amino acid moiety,            wherein an amide coupling agent is employed in the reaction;            and        -   (i) a moiety that is the product of the reaction of a            substituted thiourea moiety and a 1-methyl- or            1-phenyl-2-halopyridinium salt, preferably            2-chloro-1-methylpyridinium iodide, which iodide is also            known as Mukaima's reagent;        -   to form a compound of formula Ia′:    -   (2) optionally removing said protecting group from said —X² to        yield a compound of formula Ib′;    -   (3) optionally coupling said compound of formula Ib′ or a salt        of such a compound:    -   with a compound of formula XI:        R¹-A  XI    -   wherein one or more functional groups comprising R¹ are        optionally protected by chemical protecting groups; and    -   wherein A is a moiety containing an electrophilic reactive        center as defined above;    -   to form a compound of formula Ic′:    -   (4) chemically reducing said compound of formula Ic′ to give a        compound of formula Id′:    -   (5) optionally reacting said compound of formula Id′ with:        -   (a) an aldehyde or ketone under reductive amination            conditions; or        -   (b) alkylating the aniline nitrogen with an alkyl moiety            having a leaving group.

To form a compound of formula Ie′:

Reagents which would effect a reductive amination, include for example,sodium cyanoborohydride in the presence of a weak acid such as aceticacid.

Alkylations of the aniline nitrogen of Id′ may be accomplished withalkyl halides or alkyl mesylates.

-   -   (6) reacting said compound of formula Ie′ with an ester of        chlorosulfonylacetic acid, preferably        methylchlorosulfonylacetate or ethylchlorosulfonylacetate, to        give a compound of formula If′:    -   (7) hydrolysing said compound of formula If, to give a compound        of formula Ig′:    -   (8) reacting said compound of formula Ig′ with an aryl aldehyde,        H:    -   and    -   (9) optionally removing said protecting groups protecting        functionalities comprising R¹ to form a compound of formula I:

In another embodiment, a process for producing a compound of formula IVis provided. The process comprises

-   -   (1) coupling a compound of formula Ia′        with a compound of formula XII        R¹A¹  XII    -   wherein one or more functional groups comprising R¹ are        optionally protected by chemical protecting groups; and    -   wherein A¹ is a carboxylic acid moiety containing a leaving        group;    -   to give a compound of formula IVa:    -   (2) optionally:        -   (a) when —X² is —NH₂ protected with a protecting group,            removing said protecting group from said —X² to yield a            compound of formula IVb; or        -   (b) when —X² is —NO₂, chemically reducing said —NO₂ to —NH₂,            to form a compound of formula IVb:    -   (3) optionally coupling said compound of formula IVb or a salt        of such a compound:    -   with a compound of formula XI:        R¹-A  XI    -   wherein one or more functional groups comprising R¹ are        optionally protected by chemical protecting groups; and A is a        moiety containing an electrophilic reactive center defined as        above; and    -   (4) optionally removing said protecting groups protecting        functionalities comprising R¹ to form a compound of formula IV,        or a salt of such a compound:

According to another embodiment of the invention, a process forproducing a compound according to formula V is provided. The processcomprises:

-   -   (1) coupling a compound of formula IIIa′:    -   with        -   (a) a compound of formula XIII            R¹-A²  XIII    -   wherein one or more functional groups comprising R¹ are        optionally protected by chemical protecting groups; and wherein        A² is a carboxylic acid moiety; and        -   (b) a coupling reagent such as diisopropylcarbodiimide;    -   to give a compound of Va:    -   (2) optionally:        -   (a) when —X² is —NH₂ protected with a protecting group;            removing said protecting group from said —X² to yield a            compound of formula Vb; or        -   (b) when —X² is —NO₂, chemically reducing said —NO₂ to —NH₂        -   to form a compound of formula Vb:    -   (3) optionally coupling said compound of formula IVb or a salt        of such a compound:    -   with a compound of formula XI:        R¹-A  XI    -   wherein one or more functional groups comprising R¹ are        optionally protected by chemical protecting groups; and    -   wherein A is a moiety containing an electrophilic reactive        center as defined above; and    -   (4) optionally removing said protecting groups used in the        synthesis such as tert-butoxy carbonyl (t-Boc) or        9-fluorenyl-methoxycarbonyl (Fmoc);    -   to form a compound of formula V, or a salt of such a compound:

Amide coupling reagents used to couple unactivated carboxylic acids toanilinic amino groups and amino groups associated with peptidic R¹substituents, include for example, reagents such as diisopropylcarbodiimide (DIC) andO-(7-azabenzotriazol-1-yl)—N,N,N′,N′-tetramethyluroniumhexafluorophosphate (HATU).

In a further embodiment of the invention, a process for producing acompound according to formula VI is provided, comprising:

-   -   (1) coupling a compound of formula IIIa′:    -   with a compound of formula XIV:        R¹-A³  XIV    -   wherein one or more functional groups comprising R¹ are        optionally protected by chemical protecting groups; and    -   wherein A³ is a sulfonyl chloride moiety;    -   to give a compound of VIa:    -   (2) optionally:        -   (a) when —X² is —NH₂ protected with a protecting group,            removing said protecting group from —X² to yield a compound            of formula VIb; or        -   (b) when —X² is —NO₂, chemically reducing said —NO₂ to —NH₂,        -   to form a compound of formula VIb:    -   (3) optionally coupling said compound of formula VIb or a salt        of such a compound:    -   with a compound of formula XI:        R¹-A  XI    -   wherein one or more functional groups comprising R¹ are        optionally protected by chemical protecting groups; and    -   wherein A comprises a moiety containing an electrophilic        reactive center as defined above; and.    -   (4) optionally removing said protecting groups to form a        compound of formula VI, or a salt of such a compound:

In another embodiment of the invention, a process for producing acompound according to formula VII is provided, comprising:

-   -   (1) coupling a compound of formula IIIa′    -   with a compound of formula XV:        R¹-A⁴  XV    -   wherein one or more functional groups comprising R¹ are        optionally protected by chemical protecting groups; and    -   wherein A⁴ is moiety which is a reactive intermediate produce of        a substituted thiourea, such as        N,N′-bis-(tert-butoxycarbonyl)thiourea and a 1-methyl- or        1-phenyl-2-halopyridinium salt, preferably        2-chloro-1-methylpyridinium iodide;    -   to give a compound of VIIa:    -   (2) optionally:        -   (a) when —X² is —NH₂ protected with a protecting group,            removing said protecting group from —X² to yield a compound            of formula VIb; or        -   (b) when —X² is —NO₂, chemically reducing said —NO₂ to —NH₂        -   to form a compound of formula VIIb:    -   (3) optionally coupling said compound of formula VIIb or a salt        of such a compound:    -   with a compound of formula XI:        R¹-A  XI    -   wherein one or more functional groups comprising R¹ are        optionally protected by chemical protecting groups; and    -   wherein A comprises a moiety containing an electrophilic        reactive center as defined above; and    -   (4) optionally removing said protecting groups to form a        compound of formula VII, or a salt of such a compound:

In another embodiment of the invention, a process for producing acompound according to formula VIII is provided, comprising

-   -   (1) coupling a compound of formula IIIa′:    -   with a compound of formula XVI        R¹-A⁵  XVI    -   wherein one or more functional groups comprising R¹ are        optionally protected by chemical protecting groups; and    -   wherein A⁵ is an alkyl moiety containing a leaving group;    -   to give a compound of Villa:    -   (2) optionally        -   (a) when —X² is —NH₂ protected with a protecting group,            removing said protecting group from —X² to yield a compound            of formula VIIIb; or        -   (b) when —X² is —NO₂, chemically reducing said —NO₂ to —NH₂,        -   to form a compound of formula VIIIb:    -   (3) optionally coupling said compound of formula VIIIb or a salt        of such a compound:    -   with a compound of formula X[:        R¹-A  XI    -   wherein one or more functional groups comprising R¹ are        optionally protected by chemical protecting groups; and    -   wherein A comprises a moiety containing an electrophilic        reactive center as defined above; and    -   (4) optionally removing said protecting groups to form a        compound of formula VIII, or a salt of such a compound:

Appropriate leaving groups for alkyl moieties include for example,groups such as halides, mesylates or tosylates.

In a further embodiment of the invention, a process for producing acompound of formula IX is provided, comprising:

-   -   (1) coupling a compound of formula IIIa′    -   wherein R² is —H;    -   with a compound of formula XVII        R¹-A⁶  XVII    -   wherein one or more functional groups comprising R¹ are        optionally protected by chemical protecting groups; and    -   wherein A⁶ is a moiety containing an aldehyde or ketone moiety,        a hydrate thereof, or a ketal or acetal thereof;    -   to give a compound of IXa:    -   (2) optionally        -   (a) when —X² is —NH₂ protected with a protecting group,            removing said protecting group from —X² to yield a compound            of formula IXb; or        -   (b) when —X² is —NO₂, chemically reducing said —NO₂ to —NH₂,        -   to form a compound of formula IXb:    -   (3) optionally coupling said compound of formula IXb or a salt        of such a compound:    -   with a compound of formula E:        R¹-A  XI    -   wherein one or more functional groups comprising R¹ are        optionally protected by chemical protecting groups; and    -   wherein A comprises a moiety containing an electrophilic        reactive center as defined above; and    -   (4) optionally removing said protecting groups to form a        compound of formula IX, or a salt of such a compound:

In another embodiment of the invention, a process for producing acompound of formula X is provided, comprising:

-   -   (1) coupling a compound of formula IIIa′:    -   with a compound of formula XVIII        R¹-A⁷  XVIII        wherein one or more functional groups comprising R¹ are        optionally protected by chemical protecting groups; and        wherein    -   (a) if A⁷ is a cyanate moiety, then R¹ is selected from the        group consisting of —H, (C₁-C₆)alkyl and aryl; and R⁴ is —H; and    -   b) if A⁷ is a carbamic acid moiety activated with a leaving        group, then R¹ and R⁴ of formula X are as defined above;    -   to give a compound of the formula Xa:    -   (2) optionally:        -   (a) when —X² is —NH₂ protected with a protecting group,            removing said protecting group from —X² to yield a compound            of formula Xb; or        -   (b) when —X² is —NO₂, chemically reducing said —NO₂ to —NH₂,            to form a compound of formula Xb:    -   (3) optionally coupling said 5-NH₂ compound of formula Xb or a        salt of such a compound:    -   with a compound of formula XI        R¹-A  XI    -   wherein one or more functional groups comprising R¹ are        optionally protected by chemical protecting groups; and    -   wherein A is a moiety containing an electrophilic reactive        center as defined above; and    -   (4) optionally removing said protecting groups to form a        compound of formula X, or a salt of such a compound:

In yet another embodiment of the invention, a conjugate of the formulaI-L-Ab is provided wherein I is a compound of formula I; Ab is anantibody; and -L- is a single bond or a linking group covalently linkingsaid compound of formula I to said antibody.

In a another embodiment of the invention, a conjugate of the formulan-L-Ab is provided wherein III is a compound of formula m; Ab is anantibody; and -L- is a single bond or a linking group covalently linkingsaid compound of formula III to said antibody.

In a further embodiment of the invention, a conjugate of the formulaI′-L-Ab is provided wherein I′ is a compound of formula I′; Ab is anantibody; and -L- is a single bond or a linking group covalently linkingsaid compound of formula I′ to said antibody.

In a preferred sub-embodiment of the aforesaid conjugates of theformulae I-L-Ab, I′-L-Ab and III-L-Ab, said antibody (Ab) is amonoclonal antibody or a monospecific polyclonal antibody.

In a more preferred sub-embodiment of the aforesaid conjugates of theformulae I-L-Ab, I′-L-Ab and I-L-Ab, the aforesaid antibody (Ab) is atumor-specific antibody.

In yet a further embodiment of the present invention, there is provideda compound of formula I derivatized as a substrate for a β-lactamaseenzyme.

A pharmaceutical composition is also provided comprising apharmaceutically acceptable carrier and one or more compounds of formulaI above, or a pharmaceutically acceptable salt of such compound.

A pharmaceutical composition is additionally provided, comprising apharmaceutically acceptable carrier and at least one conjugate accordingto formula I-L-Ab, I′-L-Ab or III-L-Ab.

According to another embodiment of the invention, a method of treatingan individual for a proliferative disorder, particularly cancer, isprovided, comprising administering to said individual an effectiveamount of a compound according to formula I, or a pharmaceuticallyacceptable salt of such compound, alone or in combination with apharmaceutically acceptable carrier.

In another embodiment, a method of treating an individual an individualfor a proliferative disorder, particularly cancer, is provided,comprising administering to said individual an effective amount of atleast one conjugate of the formula I-L-Ab, I′-L-Ab or III-L-Ab.

In another embodiment of the invention, a method of inhibiting growth oftumor cells in an individual afflicted with cancer is providedcomprising administering to said individual an effective amount of acompound according to formula I, or a pharmaceutically acceptable saltof such compound, alone or in combination with a pharmaceuticallyacceptable carrier.

In another embodiment of the invention, a method of inhibiting growth oftumor cells in an individual afflicted with cancer is providedcomprising administering to said individual an effective amount of atleast one conjugate of the formula I-L-Ab, I′-L-Ab or III-L-Ab, alone orin combination with a pharmaceutically acceptable carrier.

In another embodiment, a method of inducing apoptosis of cancer cells,more preferably tumor cells, in an individual afflicted with cancer isprovided, comprising administering to said individual an effectiveamount of a compound according to formula I, or a pharmaceuticallyacceptable salt of such compound, alone or in combination with apharmaceutically acceptable carrier.

In another embodiment, a method of inducing apoptosis of cancer cells,more preferably tumor cells, in an individual afflicted with cancer isprovided, comprising administering to said individual an effectiveamount of at least one conjugate of the formula I-L-Ab, I′-L-Ab orIII-L-Ab, alone or in combination with a pharmaceutically acceptablecarrier.

The amino-substituted styryl sulfonanilides of the invention arecharacterized by cis-trans isomerism resulting from the presence of adouble bond. The compounds are named according to the Cahn-Ingold-Prelogsystem, the IUPAC 1974 Recommendations, Section E: Stereochemistry, inNomenclature of Organic Chemistry, John Wiley & Sons, Inc., New York,N.Y., 4th ed., 1992, p. 127-138. Using this system of nomenclature, thefour groups about a double bond are prioritized according to a series ofrules. Then, that isomer with the two higher ranking groups on the sameside of the double bond is designated Z (for the German word “zusammen”,meaning together). The other isomer, in which the two higher rankinggroups are on opposite sides of the double bond, is designated E (forthe German word “entgegen”, which means “opposite”). The compounds ofthe present invention have the E configuration as shown below.

The term “acyl” means a radical of the general formula —C(═O)—R, wherein—R is hydrogen, hydrocarbyl, amino or alkoxy.” Examples include forexample, acetyl (—C(═O)CH₃), propionyl(—C(═O)CH₂CH₃),benzoyl(—C(═O)C₆H₅). Phenylacetyl (—C(═O)CH₂C₆H₅), carboethoxy(—CO₂Et),and dimethylcarbamoyl(—C(═O)N(CH₃)₂).

The term “alkyl”, by itself or as part of another substituent means,unless otherwise stated, a straight, branched or cyclic chainhydrocarbon radical, including di- and multi-radicals, having the numberof carbon atoms designated (i.e. C₁-C₆ means one to six carbons) andincludes straight, branched chain or cyclic groups. Examples include:methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl,neopentyl, hexyl, cyclohexyl and cyclopropylmethyl. Most preferred is(C₁-C₃)alkyl, particularly ethyl, methyl and isopropyl.

The term “alkylene”, by itself or as part of another substituent means,unless otherwise stated, a divalent straight, branched or cyclic chainhydrocarbon radical.

The term “alkoxy” employed alone or in combination with other termsmeans, unless otherwise stated, an alkyl group having the designatednumber of carbon atoms, as defined above, connected to the rest of themolecule via an oxygen atom, such as, for example, methoxy, ethoxy,1-propoxy, 2-propoxy(isopropoxy) and the higher homologs and isomers.Preferred are (C₁-C₃)alkoxy, particularly ethoxy and methoxy.

The term “alkenyl” employed alone or in combination with other terms,means, unless otherwise stated, a stable monounsaturated ordi-unsaturated hydrocarbon radical straight chain, branched chain orcyclic hydrocarbon group having the stated number of carbon atoms.Examples include vinyl, propenyl(allyl), crotyl, isopentenyl,butadienyl, 1,3-i, 1,4-pentadienyl, cyclopentenyl, cyclopentadienyl andthe higher homologs and isomers. A divalent radical derived from analkene is exemplified by —CH═CH—CH₂—.

The term “amine” or “amino” refers to radicals of the general formula—NRR′, wherein R and R′ are independently selected from hydrogen or ahydrocarbyl radical, or wherein R and R′ combined form a heterocyle.Examples of amino groups include: —NH₂, methyl amino, diethyl amino,anilino, benzyl amino, piperidinyl, piperazinyl and indolinyl.

The term “carbamyl” means the group —C(═O)NRR′, wherein R and R′ areindependently selected from hydrogen or a hydrocarbyl radical, orwherein R and R′ combined form a heterocyle. Examples of carbamyl groupsinclude: —C(═O)NH₂ and —C(—O)N(CH₃)₂.

The term “carboxy(C₁-C₃)alkoxy” means a radical in which the carboxygroup —COOH is attached to a carbon of a straight or branched chainalkoxy group containing one to three carbon atoms. The radical thuscontains up to four carbon atoms. Examples include: —O(CH₂)₃CO₂H and—O(CH₂)₂CO₂H.

The term “cycloalkyl” refers to ring-containing alkyl radicals;

-   -   The term “heteroalkyl” by itself or in combination with another        term means, unless otherwise stated, a stable straight or        branched chain radical consisting of the stated number of carbon        atoms and one or two heteroatoms selected from the group        consisting of O, N, and S, and wherein the nitrogen and sulfur        atoms may be optionally oxidized and the nitrogen heteroatom may        be optionally quaternized. The heteroatom(s) may be placed at        any position of the heteroalkyl group, including between the        rest of the heteroalkyl group and the fragment to which it is        attached, as well as attached to the most distal carbon atom in        the heteroalkyl group. Examples include: —O—CH₂—CH₂—CH₃,        —CH₂—CH₂CH₂—OH, —CH₂—CH₂—NH—CH₃, —CH₂—S—CH₂—CH₃, and        —CH₂CH₂—S(═O)—CH₃. Up to two heteroatoms may be consecutive,        such as, for example, —CH₂—NH—OCH₃.

The term “heteroalkenyl” by itself or in combination with another termmeans, unless otherwise stated, a stable straight or branched chainmonounsaturated or di-unsaturated hydrocarbon radical consisting of thestated number of carbon atoms and one or two heteroatoms selected fromthe group consisting of O, N, and S, and wherein the nitrogen and sulfuratoms may optionally be oxidized and the nitrogen heteroatom mayoptionally be quaternized. Up to two heteroatoms may be placedconsecutively. Examples include —CH═CH—O—CH₃, —CH═CH—CH₂—OH,—CH₂—CH═N—OCH₃, —CH═CH—N(CH₃)—CH₃, and —CH₂—CH═CH—CH₂—SH.

The term “hydroxyalkyl” means an alkyl radical wherein one or more ofthe carbon atoms is substituted with hydroxy. Examples include—CH₂CH(OH)CH₃ and —CH₂CH₂OH.

The terms “halo” or “halogen” by themselves or as part of anothersubstituent mean, unless otherwise stated, a fluorine, chlorine,bromine, or iodine atom.

The term “di(C₁-C₆)alkylamino(C₂-C₆)alkoxy” means (alkyl)₂N(CH₂)_(n)O—wherein the two alkyl chains connected to the nitrogen atomindependently contain from one to six carbon atoms, preferably from oneto three carbon atoms, and n is an integer from 2 to 6. Preferably, n is2 or 3. Most preferably, n is 2, and the alkyl groups are methyl, thatis, the group is the dimethylaminoethoxy group, (CH₃)₂NCH₂CH₂O—.

The term “phosphonato” means the group —PO(OH)₂.

The term “sulfamyl” means the group —SO₂NRR′, wherein R and R′ areindependently selected from hydrogen or a hydrocarbyl radical, orwherein R and R′ combined form a heterocycle. Examples of sulfamylgroups include: —SO₂NH₂, —SO₂N(CH₃)₂ and —SO₂NH(C₆H₅).

The term “aromatic” refers to a carbocycle or heterocycle having one ormore polyunsaturated rings having aromatic character (4n+2) delocalizedπ (pi) electrons).

The term “aryl” employed alone or in combination with other terms,means, unless otherwise stated, a carbocyclic aromatic system containingone or more rings (typically one, two or three rings) wherein such ringsmay be attached together in a pendent manner, such as a biphenyl, or maybe fused, such as naphthalene. Examples include phenyl; anthracyl; andnaphthyl.

The term “aryl-(C₁-C₃)alkyl” means a radical wherein a one to threecarbon alkylene chain is attached to an aryl group, e.g.,—CH₂CH₂-phenyl. Similarly, the term “heteroaryl-(C₁-C₃)alkyl” means aradical wherein a one to three carbon alkylene chain is attached to aheteroaryl group, e.g., —CH₂CH₂-pyridyl. The term “substitutedaryl-(C₁-C₃)alkyl” means an aryl-(C₁-C₃)alkyl radical in which the arylgroup is substituted. The term “substituted heteroaryl-(C₁-C₃)alkyl”means a heteroaryl-(C₁-C₃)alkyl radical in which the heteroaryl group issubstituted.

The term “heterocycle” or “heterocyclyl” or “heterocyclic” by itself oras part of another substituent means; unless otherwise stated, anunsubstituted or substituted, stable, mono- or multicyclic heterocyclicring system which consists of carbon atoms and at least one heteroatomselected from the group consisting of N, O, and S, and wherein thenitrogen and sulfur heteroatoms may be optionally oxidized, and thenitrogen atom may be optionally quaternized. The heterocyclic system maybe attached, unless otherwise stated, at any heteroatom or carbon atomwhich affords a stable structure.

The term “heteroaryl” or “heteroaromatic” refers to a heterocycle havingaromatic character.

Examples of non-aromatic heterocycles include monocyclic groups such as:Aziridine, oxirane, thiirane, azetidine, oxetane, thietane, pyrrolidine,pyrroline, imidazoline, pyrazolidine, dioxolane, sulfolane,2,3-dihydrofuran, 2,5-dihydrofuran, tetrahydrofuran, thiophane,piperidine, 1,2,3,6-tetrahydropyridine, 1,4-dihydropyridine, piperazine,morpholine, thiomorpholine, pyran, 2,3-dihydropyran, tetrahydropyran,1,4-dioxane, 1,3-dioxane, homopiperazine, homopiperidine, 1,3-dioxepane,4,7-dihydro-1,3-dioxepin and hexamethyleneoxide.

Examples of heteroaryl groups include: Pyridyl, pyrazinyl, pyrimidinyl,particularly 2- and 4-pyrimidyl, pyridazinyl, thienyl, furyl, pyrrolyl,particularly 2-pyrrolyl, imidazolyl, thiazolyl, oxazolyl, pyrazolyl,particularly 3- and 5-pyrazolyl, isothiazolyl, 1,2,3-traizolyl,1,2,4-triazolyl, 1,3,4-triazolyl, tetrazolyl, 1,2,3-thiadiazolyl,1,2,3-oxadiazolyl, 1,3,4-thiadiazolyl and 1,3,4-oxadiazolyl.

Examples of polycyclic heterocycles include: Indolyl, particularly 3-,4-, 5-, 6- and 7-indolyl, indolinyl, quinolyl, tetrahydroquinolyl,isoquinolyl, particularly 1- and 5-isoquinolyl, tetrahydroisoquinolyl,cinnolinyl, quinoxalinyl, particularly 2- and 5-quinoxalinyl,quinazolinyl, 1,4-benzodioxanyl, coumarin, dihydrocoumarin, benzofuryl,particularly 3-, 4-, 5-, 6- and 7-benzofuryl, 2,3-dihydrobenzofuryl,1,2-benzisoxazolyl, benzothienyl, particularly 3-, 4-, 5-, 6-, and7-benzothienyl, benzoxazolyl, benzthiazolyl, particularly2-benzothiazolyl and 5-benzothiazolyl, purinyl, benzimidazolyl,particularly 2-benzimidazolyl, benztriazolyl, thioxanthinyl, carbazolyl,carbolinyl, acridinyl, pyrrolizidinyl, and quinolizidinyl.

The aforementioned listing of heterocyclyl and heteroaryl moieties isintended to be representative, not limiting.

The term “hydrocarbyl” refers to any moiety comprising only hydrogen andcarbon atoms.

The term “substituted” means that an atom or group of atoms has replacedhydrogen as the substituent attached to another group. For aryl andheteroaryl groups, the term “substituted” refers to any level ofsubstitution, namely mono-, di-, tri-, tetra-, or penta-substitution,where such substitution is permitted. The substituents are independentlyselected, and substitution may be at any chemically accessible position.

Where a substituent is an alkyl or alkoxy group, the carbon chain may bebranched, straight or cyclic, with straight being preferred.

The term “antibody” is intended to encompass not only intactantigen-binding immunoglobulin molecules, but also to includeantigen-binding fragments thereof such as Fab, Fab′ and F(ab′)₂fragments, or any other fragment retaining the antigen-binding abilityof an intact antibody.

The term “humanized antibody” refers to an antibody that has itscomplementary determining regions (CDR's) derived from a non-humanspecies immunoglobulin, and the remainder of the antibody moleculederived from a human immunoglobulin.

The term “chimeric antibody” means an antibody comprising a variableregion and a constant region derived from different species.

The term “humanized chimeric antibody” is meant a chimeric antibody inwhich at least the constant region is human-derived.

The term “monospecific polyclonal antibody” means an antibodypreparation comprising multiple antibody species having specificity fora single antigen.

The term “monovalent peptidyl moiety” refers to a peptide radical as asubstituent on a molecule of formula I. Such a radical has a chemicalstructure that varies from the structure of the corresponding peptide inthat the structural component of the peptide, ie., an alpha amino group,a sidechain amino group, an alpha carboxyl group or a sidechain carboxylgroup, will form a different functionality when bonded to the moleculeof which it is to be a substituent. For example, when a peptide as shownbelow:

-   -   H₂N-Val-Pro-Ala-COOH        is a substituent on a compound of formula I, and said peptide is        coupled to a compound of formula I such that a carboxyl moiety        of said peptide is coupled to a free amine moiety on formula I,        there is a functional elimination of H₂O that results in the        formation of an amide bond. As a practical result, the        corresponding monovalent peptidyl substituent will be as shown        to the left of the dotted line in the depiction below of the        aforementioned peptide bonded to a compound of formula I:

The term “effective amount” when used to describe therapy to a patientsuffering from a proliferative disorder, refers to the amount of acompound of formula I that inhibits the growth of tumor cells oralternatively induces apoptosis of cancer cells, preferably tumor cells,resulting in a therapeutically useful and selective cytotoxic effect onproliferative cells when administered to a patient suffering from acancer or other disorder which manifests abnormal cellularproliferation.

DETAILED DESCRIPTION OF THE INVENTION

According to the present invention, amino-substituted sulfonanilides andsalts thereof are believed to selectively inhibit proliferation ofcancer cells, and kill various tumor cell types without killing normalcells. Cells are killed at concentrations where normal cells may betemporarily growth-arrested but not killed.

The amino-substituted sulfonanilides compounds of the invention arebelieved to inhibit the proliferation of tumor cells, and for somecompounds, induce cell death. Cell death results from the induction ofapoptosis. The compounds are believed effective against a broad range oftumor types, including but not limited to the following: breast,prostate, ovarian, lung, colorectal, brain (i.e, glioma) and renal. Thecompounds are also effective against leukemic cells.

The amino-substituted sulfonanilides compounds are also believed usefulin the treatment of non-cancer proliferative disorders, including butnot limited to the following: hemangiomatosis in newborn, secondaryprogressive multiple sclerosis, chronic progressive myelodegenerativedisease, neurofibromatosis, ganglioneuromatosis, keloid formation,Pagets Disease of the bone, fibrocystic disease of the breast, Peroniesand Duputren's fibrosis, restenosis and cirrhosis.

The amino-substituted sulfonanilides may be prepared by one of twogeneral methods. In the synthesis methods to follow, reference to “Ar”is intended to include substituted and unsubstituted aryl, and alsosubstituted and unsubstituted heteroaryl.

General Mathod A as outlined in Scheme 1, utilizes a Knoevenagel-typecondensation according to Oliver et al., Synthesis 321-322 (May 1975).This synthesis relies on the condensation of an arylaminosulfonylaceticacid intermediate G with an appropriate aryl aldehyde H. The entiredisclosure of Oliver et al. is incorporated herein by reference.

According to Scheme 1, a methyl (or ethyl) β-chlorosulfonylacetateintermediate E is prepared from methyl (or ethyl) bromoacetate(R′=methyl or ethyl). To do this, methyl (or ethyl) bromoacetate isreacted with sodium sulfate to form the sodium sulfoacetate intermediateNa₂OSO₂CH₂CO₂R′. Potassium sulfate may be used as a substitute forsodium sulfate. The sodium sulfoacetate intermediate is then reactedwith a chlorinating agent, preferably PCl₅, to form the methyl (orethyl) chlorosulfonylacetate intermediate E. Reaction of intermediate Ewith the aromatic amine C yields the anilinosulfonylacetate intermediateF. The latter reaction is conducted in a nonprotic solvent in thepresence of a base. The same compound may serve as both the nonproticsolvent and the base. Such dual-function solvents include, for example,pyridine, substituted pyridines, trimethylamine, triethylamine andDIPEA. The anilinosulfonylacetate F is then converted to thecorresponding anilinosulfonylacetic acid compound G by any base capableof hydrolyzing the ester function of F to an acid. Such bases includeKOH and NaOH, for example. In the final step, the anilinosulfonylaceticacid compound is condensed with an aromatic aldehyde H in the presenceof a basic catalyst via a Knoevenagel reaction and decarboxylation of anintermediate. Basic catalysts include, for example, pyridine andbenzylamine. The reaction yields the desired amino-substitutedsulfonanilide of formula I.

The following are more detailed procedures for the preparation of theformula I compounds, according to Scheme 1 (General Method A).

General Method A

Step 1: Preparation of 3-Nitro-p-Anisidine:

To a stirring solution of 4-fluoro-3-nitroaniline (10 mmol) in 30 mL ofanhydrous methanol, was added sodium methoxide, portionwise over aperiod of 15 minutes. Throughout the addition, the reaction temperaturewas maintained below 25° C. After the addition was complete, thesolution was heated to reflux for 21 hours. The reaction progress wasmonitored by TLC. When the reaction was complete, the mixture was cooledto 0° C. The pH of the mixture was adjusted to 4.0 with hydrochloricacid followed by the addition of water. The solution was then extractedwith diethylether (3×50 mL) and the combined ether extract was washedwith brine and concentrated under vacuum to yield 3-nitro-p-anisidine.(m.p.51-53° C.; 84% yield).

Step 2: Preparation of Meth l-3-nitro-4-methoxyamilinesulfonyl Acetate:

A solution of chlorosulfonyl acetylchloride (22.4 mmol) in anhydrousether (40 mL) was cooled to 0° C. Anhydrous methanol (22.5 mmol) wasadded in one portion. The reaction mixture was maintained at 0° C. for2.5 to 3 hours and the reaction progress was monitored by TLC. When thereaction was complete by TLC, the ether was removed under reducedpressure. The crude product was used in the next step without furtherpurification.

A solution of 3-nitro-p-anisidine (20 mmol) and triethylamine (20 mmol),in dichloromethane (100 mL) was stirred at 10° C. for 15 minutes. Tothis solution was added dropwise a solution of methyl chlorosulfonylacetate (20 mmol), in dichloromethane (30 mL). After the addition wascomplete, the reaction mixture was allowed to warm to room temperatureand stirred at room temperature for 3 hours. When the reaction wascomplete by TLC, water was added, and the resulting mixture was stirredfor 15 min. The organic layer was separated and concentrated to yield aviscous liquid. The crude product was purified by column chromatographyon silica, eluting with 1:1 ethylacetate/hexane. The desiredmethyl-3-nitro-4-methoxyanilinesulfonyl acetate was obtained as a whitecrystalline solid. (m.p. 115-119° C.; yield 78%).

Step 3: Preparation of 3-nitro-4-methoxy Anilinesulfonylacetic Acid:

To a round-bottomed flask was added 5.5 g of methyl4-methoxy-3-nitroanilinesulfonyl acetate. To this was added portionwisea solution of sodium hydroxide (4.88 g in 110 mL of water). Theresulting reaction mixture was stirred at room temperature for 3 h. Thereaction progress was monitored by TLC. After the reaction was complete;the mixture was cooled to 0° C. HCl (12M) was added slowly to bring themixture to pH 3.0-4.0. The acidified mixture was stirred for 20 min at0° C. An off-white solid slowly precipitated. The solid product wasseparated by filtration and dried under vacuum. (m.p. 154-156° C.; yield75%).

Step 4: Preparation of 2,4,6-Trimethoxystyryl-N-(4-methoxy-3-nitrophenyl) Sulfonamide:

A solution of 4-methoxy-3-nitroanilinesulfonylacetic acid (10 mmol) and2,4,6-trimethoxy-benzaldehyde (10 mmol) in glacial acetic acid (15 mL)was stirred at room temperature for 10 min. A catalytic amount ofbenzylamine (300 microliters) was added to the solution. The solutionwas then refluxed for 8 h. The reaction mixture was then cooled to roomtemperature. To the cooled reaction mixture was added ethyl acetate. Asolid precipitate formed and was separated by filtration. Additional ofethyl acetate (30 mL) was added and the resulting mixture was washedsequentially with saturated sodium bicarbonate, dilute HCL and brine.The organic layer was dried over anhydrous sodium sulfate and thenconcentrated under vacuum. The solid residue obtained was recrystallizedfrom 2-propanol. (m.p 177-179° C.; yield 48-52%).

Step 5: Preparation of 2,4,6-Trimethoxystyryl-N-(3-Amino-4-methoxyphenyl) Sulfonamide:

2,4,6-trimethoxystyryl-N-(4-methoxy-3-nitrophenyl)sulfonamide (7 mmol)was dissolved in ethanol (55 mL) in a round bottomed flask. Palladiumcatalyst (5% Pd/C, 275 mg) was added. Hydrazine hydrate (182 mmol) wasthen added in one porion. The resulting misture was refluxed for 5 h andthe reaction prgress was monitored by TLC. When the reaction wascomplete, the palladium catalyst was removed by filtration and thefiltrate was poured into a beaker containing ice cold water. Thesolution was stirred and a solid precipitate formed. The precipitatedmaterial was separated by filtration and dried in vacuum. (m.p.143-145;yield 48%).

Alternate Step 5: Alternate Reduction Procedure Via Sodium Dithionite

A solution of 2,4,6-trimethoxystyryl-N-(4-methoxy-3-nitrophenyl)sulfonamide (1.3 mmol) was dissolvedin a 2:1 mixture of acetone and water (10 mL) and heated to 50° C. After30 min at 50° C., sodiumdithionite (Na₂S₂O₄) (26.3 mmol) was addedslowly, and the resulting mixture was maintained at reflux (50° C.) for1 hour, and then cooled to room temperature. Water was added and aprecipitate formed. The solid product was washed with aqueous NaHCO₃,and then taken up in ethyl acetate and dried over anhydrous Na₂SO₄. Thesolvent was removed under reduced pressure and the crude product waspurified by column chromatography. (m.p. 143-145° C.)

Step 6: Method for Coupling Carboxylic Acids to(E)-2,4,6-trimethoxystyryl-N[(3-amino)-4-methoxyphenyl]sulfonamide:

A solution of(E)-2,4,6-trimethoxystyryl-N[(3-amino)-4-methoxyphenyl]sulfonamide (1mmol), aromatic or aliphatic carboxylic acid (1.5 mmol),hydroxybenzotriazole (1.5 mmol) and 1,3-diisopropylcarbodiimide (1.4mmol) in dimethylformamide (8 mL) is taken in a reaction vessel. Thereaction vessel is connected to a manual shaker and is shaken at roomtemperature for 5 h. Ethyl acetate (20 mL) is then added to the solutionand any precipitated material is removed by filtration. The solution isdried under vacuum and the residue is treated with ethanol (20 mL) togive (E)-2,4,6-trimethoxystyryl-N-[(3-aryl oralkylamido)-4-methoxyphenyl]sulfonamide.

Alternate Step 6: Coupling of Carboxylic Acid Halides or SulfonylHalides to 2,4,6-Trimethoxy styryl-N-(3-Amino-4-methoxyphenyl)Sulfonamide:

To a solution of aromatic or alphatic acid chloride or sulfonyl chloride(10 mmol) in tetrahydrofuran (40 mL) was added dropwise a solution of2,4,6-trimethoxy styryl-N-(3-amino-4-methoxyphenyl)sulfonamide (10 mmolin 10 mL of tetrahydrofuran). The resulting mixture was stirredovernight and the reaction progress was monitored by TLC. When thereaction was complete, the solvent was removed under vacuum. The residuewas taken up in dichloromethane (50 mL) and washed with water (50 mL).The sepatated dichloromethane layer was dried over anhydrous sodiumsulfate and concentrated to yield 2,4,6-trimethoxystyryl-N-3-substituted amido-4-methoxyphenyl) sulfonamide.

The synthetic sstrategy for preparation of compounds of the invention isflexible so as to allow for rearrangement of the assembly steps toaccommodate for functional group sensitivity or to allow for diversityelements at the 3- (and optionally the 5-position) anilino nitrogenswhen employing General Method A, or allow for diversification of the Arfunctionality when employing General Method B as outlined in Scheme 2below. For synthetic strategy employing General Method B, a modificationin the aniline C is required. Use of the intermediate2-alkoxy-5-nitroaniline C¹ allows for deriviatization of the 3- andoptionally the 5-position aniline nitrogens, and thereafter reactingwith sulfonyl chloride, EA hydrolysis to intermediate G′ and reactionwith an aromatic aldehyde H to yield a compound of formula I. Thesynthetic strategy of General Method B is depicted in Scheme 2 below.

The following are more detailed procedures for the preparation of theformula I compounds, according to Scheme 2 (General Method B).

General Method B:

Step 1: Acylation of an Aniline Compound

To a solution of aromatic or alphatic acid chloride (10 mmol) intetrahydrofuran (40 mL) is added drop wise a solution of2-methoxy-5-nitroaniline (10 mmol) in tetrahydrofuran (THF). Thesolution is stirred overnight and the completion of the reaction ismonitored by TLC. The solvent is removed and the residue is taken indichloromethane and washed with water. The organic layer is dried overanhydrous sodium sulfate and evaporated to give 2-amido-4-nitroanisole.

A solution of 2-amido-4-nitroanisole (1.3 mmol) in acetone water (10:5)is heated at 50° C. After 30 min, sodium hydrosulfite (Na₂S₂O₄) (26.3mmol) is added slowly, and the mixture is heated at reflux (50° C., 1h.), cooled to room temperature and water is added. The product isrinsed with NaHCO₃, and then isolated by extraction with ethyl acetate.The organic layer is dried over anhydrous Na₂SO₄. The solvent is removedunder reduced pressure and the crude product is purified by passingthrough a silica column.

Step 2: Preparation of Methyl-3-amido-4-methoxyanilinesulfonyl Acetate:

To a solution of chlorosulfonyl acetylchloride (22.4 mmol) in anhydrousether (40 mL) cooled to 0° C., anhydrous methanol (22.5 mmol) is addedin one portion. The reaction mixture is kept at that temperature for 2.5to 3 hours and the completion of the reaction is monitored by TLC. Oncethe reaction completion is established, the ether is removed underreduced pressure and proceeded to the next step without purification.

A solution of 3-amido-p-anisidine (20 mmol), triethylamine (20 mmol), indichloromethane (100 mL) is kept at 10° C. for 15 minutes. To thissolution, methyl chlorosulfonyl acetate (20 mmol) in dichloromethane (30mL) is added dropwise. After the addition is complete, the reactionmixture is stirred at room temperature for 3 h. After the reaction iscomplete (established by TLC), water is added to the reaction mixtureand stirred for 15 min. The separated organic layer is concentrated andpurified by column chromatography.

Step 3: Preparation of 3-amido-4-methoxy anilinesulfonylacetic Acid:

To a round-bottomed flask is added 5.5 g of methyl4-methoxy-3-nitroanilinesulfonyl acetate. To this a solution of sodiumhydroxide (4.88 g in 110 mL of water) is added in portions. The reactionmixture is stirred at room temperature for 3 h. After completion of thereaction (monitored by TLC), the reaction mixture is cooled to 0° C. andconc. HCl is slowly added to bring the solution to pH 3.0-4.0. Theprecipitated solid is separated and recrystallized from hot water.

Step 4: Preparation of 2,4,6-Trimethoxystyryl-N-(4-methoxy-3-amidophenyl)-Sulfonamide:

A solution of 3-amido-4-methoxy anilinesulfonylacetic acid (10 mmol) and2,4,6-trimethoxy benzaldehyde (10 mmol) in glacial acetic acid (15 mL)is stirred at room temperature for 10 min. A catalytic amount ofbenzylamine (300 microliters) is added to the solution. The solution isthen refluxed for 8 h and then the reaction mixture is cooled to roomtemperature. Ethyl acetate is then added to the reaction mixture and anysolid precipitates are separated by filtration. Additional amount (30mL) of ethyl acetate is added and washed with saturated sodiumbicarbonate, dilute HCl and brine. The organic layer is dried overanhydrous sodium sulfate and dried layer is concentrated under vacuum.The solid product obtained is recrystallized from a suitable solvent.

The compounds of the present invention may take the form of salts. Theterm “salts”, embraces salts commonly used to form alkali metal saltsand to form addition salts of free acids or free bases. The term“pharmaceutically-acceptable salt” refers to salts which possesstoxicity profiles within a range so as to have utility in pharmaceuticalapplications. Pharmaceutically unacceptable salts may nonethelesspossess properties such as high crystallinity, which have utility in thepractice of the present invention, such as for example utility in asynthetic process. Suitable pharmaceutically-acceptable acid additionsalts may be prepared from an inorganic acid or from an organic acid.Examples of such inorganic acids are hydrochloric, hydrobromic,hydroiodic, nitric, carbonic, sulfuric and phosphoric acid. Appropriateorganic acids may be selected from aliphatic, cycloaliphatic, aromatic,araliphatic, heterocyclic, carboxylic and sulfonic classes of organicacids, example of which are formic, acetic, propionic, succinic,glycolic, gluconic, lactic, malic, tartaric, citric, ascorbic,glucuronic, maleic, fumaric, pyruvic, aspartic, glutamic, benzoic,anthranilic, mesylic, salicyclic, salicyclic, 4-hydroxybenzoic,phenylacetic, mandelic, embonic (pamoic), methanesulfonic,ethanesulfonic, benzenesulfonic, pantothenic, 2-hydroxyethanesulfonic,toluenesulfonic, sulfanilic, cyclohexylaminosulfonic, stearic, algenic,beta-hydroxybutyric, salicyclic, galactaric and galacturonic acid.Examples of pharmaceutically unacceptable acid addition salts includeperchlorates and tetrafluoroborates.

Suitable pharmaceutically acceptable base addition salts of compounds offormula I include for example, metallic salts made from calcium,magnesium, potassium, sodium and zinc or organic salts made fromN,N′-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine,ethylenediamine, meglumine (N-methylglucamine) and procaine. Examples ofpharmaceutically unacceptable salts include lithium salts and cyanatesalts. All of these salts may be prepared by conventional means from thecorresponding compound of formula I by reacting, for example, theappropriate acid or base with the compound of formula I.

It will be understood that when compounds of the present inventioncontain one or more chiral centers, the compounds may exist in, and maybe isolated as pure enantiomeric or diastereomeric forms or as racemicmixtures. The present invention therefore includes any possibleenantiomers, diastereomers, racemates or mixtures thereof of formula Iwhich are biologically active in the treatment of cancer or otherproliferative disease states.

The compounds of the invention may be administered to individuals(mammals, including animals and humans) afflicted with cancer.

The compounds are also believed useful in the treatment of non-cancerproliferative disorders, that is, proliferative disorders which arecharacterized by benign indications. Such disorders may also be known as“cytoproliferative” or “hyperproliferative” in that cells are made bythe body at an atypically elevated rate. Such disorders include, but arenot limited to, the following: hemangiomatosis in new born, secondaryprogressive multiple sclerosis, chronic progressive myelodegenerativedisease, neurofibromatosis, ganglioneuromatosis, keloid formation,Pagets Disease of the bone, fibrocystic disease of the breast, Peroniesand Duputren's fibrosis, restenosis and cirrhosis.

For treating proliferative disorders, the specific dose of compoundaccording to the invention to obtain therapeutic benefit will, ofcourse, be determined by the particular circumstances of the individualpatient including, the size, weight, age and sex of the % patient, thenature and stage of the disease, the aggressiveness of the disease, andthe route of administration. For example, a daily dosage of from about0.05 to about 50 mg/kg/day may be utilized. Higher or lower doses arealso contemplated.

The amino-substituted sulfonanilide compounds may be administered fortherapeutic effect by any route, for example enteral (e.g., oral,rectal, intranasal, etc.) and parenteral administration. Parenteraladministration includes, for example, intravenous, intramuscular,intraarterial, intraperitoneal, intravaginal, intravesical (e.g., intothe bladder), intradermal, topical, subcutaneous or sublingualadministration. Also contemplated within the scope of the invention isthe instillation of drug in the body of the patient in a controlledformulation, with systemic or local release of the drug to occur at alater time. For anticancer use, the drug may be localized in a depot forcontrolled release to the circulation, or local site of tumor growth.

The compounds of the invention may be administered in the form of apharmaceutical composition, in combination with a pharmaceuticallyacceptable carrier. The active ingredient in such formulations maycomprise from 0.1 to 99.99 weight percent. By “pharmaceuticallyacceptable carrier” is meant any carrier, diluent or excipient which iscompatible with the other ingredients of the formulation and todeleterious to the recipient.

The active agent is preferably administered with a pharmaceuticallyacceptable carrier selected on the basis of the selected route ofadministration and standard pharmaceutical practice. The active agentmay be formulated into dosage forms according to standard practices inthe field of pharmaceutical preparations. See Alphonso Gennaro, ed.,Remington's Phamaceutical Sciences, 18th Ed., (1990) Mack PublishingCo., Easton, Pa. Suitable dosage forms may comprise, for example,tablets, capsules, solutions, parenteral solutions, troches,suppositories, or suspensions.

For parenteral administration, the active agent may be mixed with asuitable carrier or diluent such as water, an oil (particularly avegetable oil), ethanol, saline solution, aqueous dextrose (glucose) andrelated sugar solutions, glycerol, or a glycol such as propylene glycolor polyethylene glycol. Solutions for parenteral administrationpreferably contain a water-soluble salt of the active agent. Stabilizingagents, antioxidizing agents and preservatives may also be added.Suitable antioxidizing agents include sulfite, ascorbic acid, citricacid and its salts, and sodium EDTA. Suitable preservatives includebenzalkonium chloride, methyl- or propyl-paraben, and chlorbutanol. Thecomposition for parenteral administration may take the form of anaqueous or nonaqueous solution, dispersion, suspension or emulsion.

For oral administration, the active agent may be combined with one ormore solid inactive ingredients for the preparation of tablets,capsules, pills, powders, granules or other suitable oral dosage forms.For example, the active agent may be combined with at least oneexcipient such as fillers, binders, humectants, disintegrating agents,solution retarders, absorption accelerators, wetting agents absorbentsor lubricating agents. According to one tablet embodiment, the activeagent may be combined with carboxymethylcellulose calcium, magnesiumstearate, mannitol and starch, and then formed into tablets byconventional tableting methods.

The practice of the invention is illustrated by the followingnon-limiting examples. Representative compounds are listed in Table 4.

EXAMPLE 1(E)-2,4,6-Trimethoxystyryl-N-[(3-N,N-dimethylacetamido)-4-methoxyphenyl]sulfonamide

A solution of N,N-dimethylglycyl chloride (10 mmol) and(E)-2,4,6-trimethoxystyryl-N-[(3-aminosubstituted)-4-methoxyphenyl]sulfonamidewas reacted according to the General Method A. The product obtained waspurified by column chromatography. (yield 94.65%, m.p. 176-178° C.)

EXAMPLE 2(E)-2,4,6-Trimethoxystyryl-N-[(3-acetamido)₄-methoxyphenyl]-sulfonamide

A solution of acetyl chloride (10 mmol) and(E)-2,4,6-trimethoxystyryl-N-[(3-aminosubstituted)-4-methoxyphenyl]sulfonamidewas reacted according to the General Method A. The product obtained waspurified by column chromatography. (yield 64.5%, m.p. 296-298° C.)

EXAMPLE 3(E)-2,4,6-Trimethoxystyryl-N-[(3-amino)-4-methoxyphenyl]-sulfonamide-L-lysineamidehydrochloride A.(E)-2,4,6-Trimethoxystyryl-N-[(3-amino)-4-methoxyphenyl]sulfonamide-L-di-boc-lysineamide

A solution of(E)-2,4,6-trimethoxystyryl-N-[(3-amino)-4-methoxyphenyl]-sulfonamide (1mmol), di-boc-lysine (1.5 mmol), hydroxybenzotriazole (HOBT)(1.5 mmol)and 1,3-diisopropylcarbodiimide (DIC) (1.5 mmol) in dimethylformamide(DMF)(8 mL) was shaken in a reaction vessel at room temperature for 5hours. Ethyl acetate (20 mL) was added to the mixture and anyprecipitated solid was removed by filtration. The volatiles were removedunder vacuum and the resulting residue was triturated with ethanol (20mL) to give(E)-2,4,6-trimethoxystyryl-N-[(3-amino)-4-methoxyphenyl]sulfonamide-L-di-boc-lysineamide.

B.(E)-2,4,6-Trimethoxystyryl-N-[(3-amino)-4-methoxyphenyl]sulfonamide-L-lysineamideHydrochloride.

To a solution of(E)-2,4,6-trimethoxystyryl-N-[(3-amino)-4-methoxyphenyl]sulfonamide-L-di-boc-lysineamide(500 mg) in dichloromethane (5 ml) was added a solution of 4MHCl/dioxane (1 mL). The resulting mixture was stirred at roomtemperature for 2 hours. The precipitated salt was separated byfiltration and recrystallized from acetone to give(E)-2,4,6-trimethoxystyryl-N-[(3-amino)-4-methoxyphenyl]sulfonamide-L-lysineamidehydrochloride. (yield 44.8%, m.p. above 300° C.).

EXAMPLE 4(E)-2,4,6-Trimethoxystyryl-N-[(3-acetoxyacetamido)-4-methoxy-phenyl]sulfonamide

A solution of acetoxy acetyl chloride (10 mmol) and(E)-2,4,6-trimethoxystyryl-N-[(3-aminosubstituted)-4-methoxyphenyl]sulfonamidewas reacted according to the General Method A. The product obtained waspurified by column chromatography. (yield 64.5%, m.p. 219-222° C.)

EXAMPLE 5 (E)-2,4,6-Trimethoxystyryl-N-[(3-carboxymethylamino)-4-methoxyphenyl]sulfonamide

To a stirred solution of methyl bromoacetate (5 mmol) and sodium acetate(5 mmol) in methanol (20 mL) was added(E)-2,4,6-trimethoxystyryl-N-[(3-aminosubstituted)-4-methoxyphenyl]sulfonamide(1 mmol). The resulting mixture was heated to reflux for 12-15 h. Thereaction mixture was then cooled and poured onto water ice. A solidprecipitate formed and was separated by filtration. The product esterwas obtained in 85% yield.

The ester (1 g) was dissolved in a mixture of ethanol (8 mL) and 4%aqueous sodium hydroxide (50 mL). The resulting mixture was heated toreflux for 10 min to form a clear solution. The reaction mixture wasthen allowed to cool to room temperature and stirred at room temperaturefor 3 hours. Concentrated hydrochloric acid was then added dropwiseuntil a solid precipitate formed. The precipitate was separated byfiltration, washed with water and recrystallized from acetone:water togive(E)-2,4,6-trimethoxystyryl-N-[(3-carboxymethylamino)-4-methoxyphenyl]sulfonamidein 58.7% yield. (m.p. 166-170° C.)

EXAMPLE 6(E)-2,4,6-Trimethoxystyryl-N-[(3-hydroxyacetamido)₄-methoxy-phenyl]sulfonamide

A solution of(E2,4,6-trimethoxystyryl-N-[(3-acetoxyacetamido)-4-methoxyphenyl]sulfonamide(prepared as in Example 4) was hydrolyzed in aqueous potassium carbonateto give(E)-2,4,6-trimethoxystyryl-N-[(3-hydroxyacetamido)₄-methoxyphenyl]sulfonamide.(yield 33.6%, m.p. 182-184° C.)

EXAMPLE 7(E)-2,4,6-Trimethoxystyryl-N-[(3-chloroacetamido)-4-methoxyphenyl]-sulfonamide

A solution of chloroacetyl chloride (10 mmol) and(E)-2,4,6-trimethoxystyryl-N-[(3-aminosubstituted)-4-methoxyphenyl]sulfonamidewas reacted according to the General. Method A. The product obtained waspurified by column chromatography. (yield 68.7%, m.p. 192-194° C.

EXAMPLE 8(E)-2,4,6-Trimethoxystyryl-N-[3-(4-methylpiperazinyl)-acetamido-4-methoxyphenyl]sulfonamide

A solution of(E)-2,4,6-trimethoxystyryl-N-[(3-chloroacetamido)-4-methoxyphenyl]sulfonamide(10 mmol), N-methylpiperazine (10 mmol) and potassium carbonate (10mmol) in DMF (20 mL) was heated to reflux (80° C.) for 5 hours. Thereaction mixture was then cooled to room temperature, and water wasadded. The resulting mixture was extracted with ethylacetate. Theorganic layer was washed with water and brine and dried over sodiumsulfate. The volatiles were removed under vacuum to give(E)-2,4,6-trimethoxystyryl-N-[3-(4-methylpiperazinyl)-acetamido-4-methoxyphenyl]sulfonamidein 44.8% yield. (m.p. 137-140° C.)

EXAMPLE 9(E)-2,4,6-Trimethoxystyryl-N-[(3-trifluoroacetamido)-4-methoxy-phenyl]sulfonamide

A solution of trifluoroacetic anhydride (30 mmol) and(E)-2,4,6-trimethoxystyryl-N-[(3-aminosubstituted)₄-methoxyphenyl]sulfonamide(10 mmol) was stirred at room temperature for 2 hours. The volatileswere removed under vacuum and the resulting residue and the productobtained was purified by column chromatography. (yield 58.60%).

EXAMPLE 10(E)-2,4,6-Trimethoxystyryl-N-[(3-carboxymethylsulfamyl)₄-methoxyphenyl]sulfonamide

A solution of methyl chlorosulfonyl acetate (10 mmol) and5-nitro-2-methoxyaniline is subjected to General Method B and theproduct obtained is hydrolyzed with aqueous sodium hydroxide to give thetitle compound.

EXAMPLE 11(E)-2,4,6-Trimethoxystyryl-N-[(3-carboxyacetamido)-4-methoxy-phenyl]sulfonamide

A solution of methyl 3-chloro-3-oxopropionate (10 mmol) and5-nitro-2-methoxyaniline is subjected to General Method B and theproduct obtained is hydrolyzed with aqueous sodium hydroxide to give thetitle compound.

EXAMPLE 12(E)-2,4,6-Trimethoxystyryl-N-[(3-guanidino)-4-methoxyphenyl]-sulfonamide

To a solution of2,4,6-trimethoxystyryl-N-[(3-amino)-4-methoxyphenyl]-sulfonamide (10mmol), N,N-bis(tert-butoxycarbonyl)thiourea (12 mmol) and triethylamine(22 mmol) in dichloromethane (10 mL), is added Mukaiyama reagent(2-chloro-1-methylpyridinium iodide) (12 mmol). The reaction mixture isstirred at 25° C. until the completion of the reaction which ismonitored by TLC. Upon the completion of the reaction, the solvent isevaporated and the residue is dissolved in diethyl ether (15 mL) andwashed with water. The ethereal layer is dried over anhydrous sodiumsulfate and evaporated in a rotary evaporator to give2,4,6-trimethoxystyryl-N-[(3-di-tert-butoxyguanidino)-4-methoxyphenyl]-sulfonamide.

A solution of2,4,6-trimethoxystyryl-N-(3-di-tert-butoxyguanidino-4-methoxyphenyl)sulfonamide(1 g) is dissolved in a 1:1 mixture of dichloromethane andtrifluoroacetic acid. The reaction mixture is stirred for 3 h at roomtemperature and the solution is concentrated under vacuum. The residueis washed and concentrated several times with diethyl ether for completeremoval of trifluoroacetic acid. The residue is given a final wash withwater and the solid obtained is subjected to column chromatography(silica gel 70-325 mesh) to yield the title compound.

EXAMPLE 13(E)-2,4,6-Trimethoxystyryl-N-[3-(3,5-dinitrobenzamido)-4-methoxy-phenyl]sulfonamide

A solution of 3,5-dinitrobenzoyl chloride (10 mmol) and5-nitro-2-methoxyaniline is subjected to General Method B to give thetitle compound.

EXAMPLE 14(E)-2,4,6-Trimethoxystyryl-N-[3-(3,5-diaminobenzamido)₄-methoxy-phenyl]sulfonamide

A solution of(E)-2,4,6-trimethoxystyryl-N-[3-(3,5-dinitrobenzamido)-4-methoxyphenyl]sulfonamide(Example 5) is reduced by following the sodium hydrosulfite reductionprocedure as described in General Method B to give the title compound.

EXAMPLE 15(E)-2,4,6-Trimethoxystyryl-N-[(3-benzamido)-4-methoxyphenyl]-sulfonamide

A solution of benzoylchloride (10 mmol) and 5-nitro-2-methoxyaniline issubjected to General Method B to give the title compound.

EXAMPLE 16(E)-2,4,6-Trimethoxystyryl-N-31(4-nitrobenzamido)-4-methoxy-phenyl]sulfonamide

A solution of 4-nitrobenzoyl chloride (10 mmol) and5-nitro-2-methoxyaniline is subjected to General Method B to give thetitle compound.

EXAMPLE 17 (E)-2,4,6-Trimethoxystyryl-N-3[(4-aminobenzamido)-4-methoxy-phenyl]sulfonamide

A solution of(E)-2,4,6-trimethoxystyryl-N-[3-(4-nitrobenzamido)-4-methoxyphenyl]sulfonamide(Example 9) is reduced by following the sodium hydrosulfite reductionprocedure as described in General Method B to give the title compound.

EXAMPLE 18 (E)-2,4,6-Trimethoxystyryl-N-3[(4-nitrophenyimino)-4-methoxy-phenyl]sulfonamide

To a solution of(E)-2,4,6-trimethoxystyryl-N-[(3-amino)-4-methoxyphenyl]sulfonamide (10mmol) in methanol (40 mL) is added 4-nitrobenzaldehyde (10 mmol). Thesolution is refluxed with vigorous stirring for 5 h. The reactionmixture is cooled, diluted with water and the aqueous mixture is thenextracted twice with dichloromethane, and the organic layer is driedover anhydrous magnesium sulfate. The dried organic solution isevaporated and the residue is recrystallized to give the title compound.

EXAMPLE 19(E)-2,4,6-Trimethoxystyryl-N-[(3-amino)-4-methoxyphenyl]sulfonamide-L-serineamideStep 1:(E)-2,4,6-Trimethoxystyryl-N-[(3-amino)-4-methoxyphenyl]sulfonamide-L-Fmoc-serineamide:

A solution of(E)-2,4,6-trimethoxystyryl-N-[(3-amino)₄-methoxyphenyl]-sulfonamide (1mmol), Fmoc-Ser-OH (1.5 mmol), HOBT (1.5 mmol) and DIC (1.5 mmol) in DMF(8 mL) is taken in a reaction vessel. The reaction vessel is connectedto a manual shaker and is shaken at room temperature for 5 h. Ethylacetate (20 mL) is then added to the solution and any precipitatedmaterial is removed by filtration. The solution is dried under vacuumand the residue is treated with ethanol (20 mL) to give(E)-2,4,6-trimethoxystyryl-N-[(3-amino)-4-methoxyphenyl]sulfonamide-L-Fmoc-serineamide.

Step 2:(E)-2,4,6-Trimethoxystyryl-N-[(3-amino)-4-methoxyphenyl]sulfonamide-L-serineamide:

To a stirred solution of(E)-2,4,6-trimethoxystyryl-N-(3-amino-4-methoxyphenyl)sulfonamide-L-Fmoc-serineamide(500 mg) dichloromethane (10 mL), is added piperidine (2 mL) andstirring is continued for 2 h. The solvent is removed under vacuum andthe residue is dissolved in dichloromethane and loaded on a silica-gelcolumn. The compound is eluted with 1:1 dichloromethane and ethylacetate. The solvent is removed under vacuum to give(E)-2,4,6-trimethoxystyryl-N-[(3-amino)-4-methoxyphenyl]sulfonamide-L-serineamide.

EXAMPLE 20(E)-2,4,6-Trimethoxystyryl-N-[(3-amino)₄-methoxyphenyl]-sulfonamide-D-serineamideStep 1:(E)-2,4,6-Trimethoxystyryl-N-[(3-amino)-4-methoxyphenyl]sulfonamide-D-Fmoc-serineamide:

A solution of (E)-2,4,6-trimethoxystyryl-N-(3-amino-4-methoxyphenyl)sulfonamide (1 mmol), Fmoc-Ser-OH (1.5 mmol), HOBT (1.5 mmol) and DIC(1.5 mmol) in DMF (8 mL) is taken in a reaction vessel. The reactionvessel is connected to a manual shaker and is shaken at room temperaturefor 5 h. Ethyl acetate (20 mL) is then added to the solution and anyprecipitated material is removed by filtration. The solution is driedunder vacuum and the residue is treated with ethanol (20 mL) to give(E)-2,4,6-trimethoxystyryl-N-(3-amino-4-methoxyphenyl)sulfonamide-D-Fmα-serineamide.

Step 2:(E2,4,6-Trimethoxystyryl-N-[(3-amino)-4-methoxyphenyl]sulfonamide-D-serineamide:

To a stirred solution of(E)-2,4,6-trimethoxystyryl-N-(3-amino-4-methoxyphenyl)sulfonamide-L-Fmoc-serineamide(500 mg) dichloromethane (10 mL), is added piperidine (2 mL) andstirring is continued for 2 h. The solvent is removed under vacuum andthe residue is dissolved in dichloromethane and loaded on a silica-gelcolumn. The compound is eluted with 1:1 dichloromethane and ethylacetate. The solvent is removed under vacuum to give(E)-2,4,6-trimethoxystyryl-N-(3-amino-4-methoxyphenyl)sulfonamide-D-serineamide.

EXAMPLE 21(E)-2,4,6-Trimethoxystyryl-N-[(3-ureido)-4-methoxyphenyl]-sulfonamide

To a solution of2,4,6-trimethoxystyryl-N-(3-amino-4-methoxyphenyl)-sulfonamide (1 mmol)in glacial acetic acid (10 mL) is added an aqueous solution of potassiumcyanate (1 mmol in 2 mL of de-ionized water). The reaction mixture isstirred for 3 h at room temperature. The reaction mixture is then pouredinto de-ionized water (100 mL) and extracted with ethyl acetate for 3times. The combined organic layer is then washed with sodium bicarbonateto neutralize acetic acid and then with brine. The organic layer is thendried over anhydrous magnesium sulfate and the solvent is removed undervacuum to yield the title compound which is purified by columnchromatography.

EXAMPLE 22(E)-2,4,6-Trimethoxystyryl-N-[(3-N-methylamino)-4-methoxy-phenyl]sulfonamide

To a stirred solution of sodium acetate (5 mmol) and2,4,6-trimethoxystyryl-N-(3-amino-4-methoxyphenyl)sulfonamide (1 mmol)in methanol (20 mL), is added methyl iodide (1.5 mmol) and stirring iscontinued under reflux temperature for 12-15 h. The contents of theflask are cooled and poured into the ice water. The white productseparated out is filtered, washed with chloroform and dried under vacuumto give(E)-2,4,6-trimethoxystyryl-N-3-N-methylamino-4-methoxyphenyl)sulfonamide.

EXAMPLE 23(E)-2,4,6-Trimethoxystyryl-N-[3-(3,5-dinitrobenzenesulfamyl)-4-methoxyphenyl]sulfonamide

A solution of 2,4-dinitrobenzenesufonyl chloride (10 mmol) and5-nitro-2-methoxyaniline is subjected to General Method B to give thetitle compound.

EXAMPLE 24(E)-2,4,6-Trimethoxystyryl-N-[3-(3,5-diaminobenzene-sulfamyl)-4-methoxy-phenyl]sulfonamide

A solution of(E)-2,4,6-trimethoxystyryl-N-[32,4-dinitrobenzene-sulfamyl)₄-methoxyphenyl]sulfonamide(Example 19) is reduced following the sodium hydrosulfite reductionprocedure as described in General Method B to give the title compound.TABLE 4

Example # X Synthesis route 1 Dimethylaminoacetamido A 2 Acetamido- A 3L-Lysineamido- A 4 Acetoxyacetamido A 5 Carboxymethylamino B 6Hydroxyacetamido Hydrolysis of 4 7 Chloroacetamido- A 8(4-methylpiperazinyl)-acetamido- Aminate #7 9 trifluoroacetamido A 10Carboxymethylsulfamyl- B 11 Carboxyacetamido- B 12 Guanidino- A 133,5-dinitrobenzamido- B 14 3,5-diaminobenzamido- Reduce #13 15Benzamido- B 16 4-Nitrobenzamido- B 17 4-Aminobenzamido- Reduce #16 184-nitrophenylimino- A 19 L-serinamido- A 20 D-serinamido- A 21 Ureido- A22 Methylamino- A 23 3,5-dinitrobenzene-sulfamyl- A 243,5-diaminobenzene-sulfamyl- Reduce #23

EXAMPLE 25 Effect of Amino-Substituted Sulfonanilides on Tumor CellLines

The effect of the amino-substituted sulfonanilides on normal fibroblastsand on tumor cells may be determined by the assay described by Latham etal., Oncogene 12:827-837 (1996). Normal diploid lung human fibroblasts(HFL-1) or tumor cells (e.g., prostate, colorectal, breast, glial,pancreatic, ovarian, lung or leukemic) are plated in 6-well dishes at acell density of 1.0×10⁵ cells per 35-mm² well. The plated cells aretreated 24 hours later with various concentrations of amino-substitutedsulfonanilide dissolved in dimethyl sulfoxide (DMSO). The total numberof viable cells is determined 96 hours later by trypsinizing the wellsand counting the number of viable cells, as determined by trypan blueexclusion, using a hemacytometer. Normal HFL cells are treated with thesame compounds under the same conditions of concentration and time.Biological data for compounds of the present invention is shown in Table5 below in DU145, BT20, DLD1 and H157 tumor cell lines. A (+) in thetable indicates that the compound showed tumor cell killing activity ata concentration of less than 20 micromolar. TABLE 5 Example # X-R DU145BT20 DLD1 H157 1 3-NH—COCH₂N(CH₃)₂ + + + + 2 3-NH—COCH₃ + + + + 33-NH-L-lysine + + + + 4 3-NH—COCH₂OOCCH₃ + + + + 5 3-NH—CH₂COOH + + + +6 3-NH—COCH₂OH + + + + 7 3-NH—COCH₂Cl + + + + 83-NH—COCH₂-piperazine-N—CH₃ + + + + 9 3-NH—COCF₃ ND ND ND ND

EXAMPLE 26 Induction of Apoptosis in Tumor Cells

The following assay demonstrates the apoptotic activity of the compoundsof the invention against tumor cells.

The caspases and the ICE-family proteases are cysteine proteases whichare activated during apoptosis (Patel et al., FASEB 10:587-597, 1996).The cleavage of poly(ADP-ribose) polymerase (PARP), which is a target ofcaspase-3, apopain, and several other activated proteases, is a widelyused and accepted marker for apoptosis Nicholson et al., Nature376(6533):37-43, 1995; Lippke et al., J. Biol. Chemistry 271:1825,1996). For this assay, BT20 cells (an estrogen receptor negative breastcarcinoma) and HFL-1 cells (normal lung fibroblasts) are treated with anamino-substituted sulfonanilide according to the present invention at afinal concentration of 20 μM or dimethyl sulfoxide (DMSO) for 96 hours.The cells are then lysed in RIPA buffer and 100 μg of total cellularprotein from each sample is resolved on a 10% SDS-polyacrylamide gel.The proteins are then Western blotted onto PROTRAN filter paper (S/S)and the filter is then probed with antibody (Boehringer Mannheim)specific for PARP. This antibody recognizes both the 116 kDa full lengthPARP and the 83 kDa cleaved product. The assay shows whether the testcompound specifically activates caspases in the treated breast carcinomacell line and not in the normal cell line. The western blot showswhether only the test compound-treated BT20 cells displayed the presenceof the 83 kDa PARP cleavage product. The HFL-1 cells, treated in asimilar manner as controls, do not cleave full length PARP. BT20 cellstreated with DMSO as a control for the same amount of time do notactivate the apoptotic pathway. The results will show that the compoundsof the invention selectively kill cancer cells by activating theapoptotic pathway as indicated by the activation of the cysteineproteases, a molecular marker for apoptosis. Cells which are nottumorigenic will not undergo apoptosis but may become growth arrested atconcentrations significantly higher than the concentration necessary fortumor cell death.

All references cited herein are incorporated by reference. The presentinvention may be embodied in other specific forms without departing fromthe spirit or essential attributes thereof and, accordingly, referenceshould be made to the appended claims, rather than to the foregoingspecification, as indication the scope of the invention.

1. A compound of formula I:

wherein: Ar is selected from the group consisting of substituted andunsubstituted aryl, and substituted and unsubstituted heteroaryl; X isselected from the group consisting of (i) and (ii) below:

X¹ is selected from the group consisting of (i), (ii) and (iii) below:

wherein X¹ is optionally protected with one or more chemical protectinggroups; g is 0 or 1; each M is a bivalent connecting group independentlyselected from the group consisting of —(C₁-C₆)alkylene-,(CH₂)_(a)—V—(CH₂)_(b), —(CH₂)_(d)—W—(CH₂)_(e) and -Z-; each y isindependently selected from the group consisting of 0 and 1; each V isindependently selected from the group consisting of —C(═O)—, —C(═O)—O—,—C(═O)—(C₁-C₆)perfluoroalkylene-, —C(═S)—, —S(═O)—, —SO₂—, —C(═O)NR⁴—,—C(═S)NR⁴— and —SO₂NR⁴—; each W is independently selected from the groupconsisting of —NR⁴—, —O— and —S—; each a is independently selected fromthe group consisting of 0, 1, 2 and 3; each b is independently selectedfrom the group consisting of 0, 1, 2 and 3; each d is independentlyselected from the group consisting of 1, 2 and 3; each e isindependently selected from the group consisting of 0, 1, 2 and 3;

wherein the absolute stereochemistry of -Z- is D or L, or a mixture of Dand L; R is selected from the group consisting of —H, (C₁-C₆)alkyl,(C₁-C₆)alkoxy, (C₃-C₆)alkenyl, (C₂-C₆)heteroalkyl, (C₃-C₆)heteroalkenyl,(C₂-C₆)hydroxyalkyl, substituted aryl, unsubstituted aryl, substitutedheterocyclic, unsubstituted heterocyclic, substituted aryl(C₁-C₃)alkyl,unsubstituted aryl(C₁-C₃)alkyl, substituted heterocyclic(C₁-C₃)alkyl andunsubstituted heterocyclic(C₁-C₃)alkyl; each R^(a) is independentlyselected from the group consisting of —H, —CH₃, —(CH₂)₃—NH—C(NH₂)(═NH),—CH₂C(═O)NH₂, —CH₂COOH, —CH₂SH, —(CH₂)C(═O)—NH₂, —(CH₂)₂COOH,—CH₂-(2-imidazolyl), —CH(CH₃)—CH₂—CH₃, —CH₂CH(CH₃)₂, —(CH₂)₄—NH₂,—(CH₂)₂—S—CH₃, phenyl, CH₂-phenyl, —CH₂—OH, —CH(OH)—CH₃,—CH₂-(3-indolyl), —CH₂-(4-hydroxyphenyl), —CH(CH₃)₂ and —CH₂—CH₃; andincludes compounds wherein R^(a) and R¹ combine to form a 5-, 6- or7-membered heterocyclic ring; each R¹ is independently selected from thegroup consisting of —H, —(C₁-C₆)perfluoroalkyl, unsubstituted aryl,substituted aryl, substituted heterocyclic, unsubstituted heterocyclic,—CO₂R⁵, —C(═O)NR⁴ ₂, —CR⁴R⁶R⁷, —C(═NH)—NR⁴ ₂ and a monovalent peptidylmoiety with a molecular weight of less than 1000; provided that when yis 0 and R¹ is —CO₂R⁵, R⁵ is not —H; each R² is independently selectedfrom the group consisting of —H, —(C₁-C₆)alkyl, and aryl(C₁-C₃)alkyl,wherein —R² and —(M)_(y)—R¹ may optionally be linked covalently to forma 5-, 6- or 7-membered substituted or unsubstituted heterocycle; R³ isindependently selected from —(C₁-C₆)alkyl; each R⁴ is independentlyselected from the group consisting of —H, and —(C₁-C₆)alkyl; wherein:when R⁴ and R¹ are bonded to the same nitrogen atom, R¹ and R⁴ maycombine to form a heterocycle; and when two R⁴ groups are geminallybonded to the same nitrogen, the two R⁴ groups may combine to form aheterocycle; each R⁵ is independently selected from the group consistingof —H, —(C₁-C₆)alkyl and —(C₁-C₆)acyl; each R⁶ is independently selectedfrom the group consisting of —H, C₁-C₆)alkyl, —CO₂R⁵, —C(═O)R⁷, —OR⁵,—SR⁴, —(C—C₃)alkoxy, —(C₁-C₃)alkylthio, guanidino, —NR⁴ ₂, phenyl,substituted phenyl, heterocyclic, substituted heterocyclic and halogen;each R⁷ is independently selected from the group consisting of —H,halogen, —(C₁-C₆)alkyl, —NR⁴ ₂ and heterocycles containing two nitrogenatoms; and wherein the substituents for the substituted aryl andsubstituted heterocyclic groups comprising or included within Ar, R, R¹,R^(a), R⁶ and R⁷, are independently selected from the group consistingof halogen, (C₁-C₆)alkyl, (C₁-C₆)alkoxy, —NO₂, —C≡N, —CO₂R⁵,—C(═O)O(C₁-C₃)alkyl, —OH, —(C₂-C₆)—OH, phosphonato, —NR⁴ ₂,—NHC(═O)(C₁-C₆)alkyl, sulfamyl, carbamyl, —OC(═O)(C₁-C₃)alkyl,—O(C₂-C₆)—N((C₁-C₆)alkyl)₂ and —CF₃; provided (1) when R¹ is amonovalent peptidyl moiety of molecular weight less than 1000 and V is—C(═O), —C(═S, —S(—O)— or —SO₂—, and b is 0; then said peptidyl moietyis coupled to M through the peptide's amino terminus or through asidechain amino group to form an amide, thioamide, sulfinamide orsulfonamide respectively; (2) when R¹ is a monovalent peptidyl moiety ofmolecular weight less than 1000 and V is —C(═O)NR³—, —SO₂NR³—, or —NR⁴—,and b is 0, then said peptidyl moiety is coupled to M through thepeptide's carboxy terminus or through a sidechain carboxyl group to forman imide, sulfonimide, or carboxamide respectively; and (3) when R¹ is amonovalent peptidyl moiety of molecular weight less than 1000 and W is—S— or —O—, and d is 0, then said peptidyl moiety is coupled to Mthrough the peptide's carboxy terminus or through a sidechain carboxylgroup to form a carbothioic acid ester or the carboxylic esterrespectively; or a salt of such a compound.
 2. A compound according toclaim 1 selected from the group consisting of:(E)-2,4,6-Trimethoxystyryl-N-[(3-trifluoroacetamido)-4-methoxy-phenyl]sulfonamide;and(E)-2,4,6-Trimethoxystyryl-N-[(3-acetoxyacetamido)4-methoxyphenyl]-sulfonamide;or a salt of such a compound.
 3. A compound according to claim 1 havingthe formula III:

wherein: Ar, X¹, R, R², R³ and g are defined as in claim 1; or a salt ofsuch a compound.
 4. A compound according to claim 3 having the formulaIIIa:

wherein: Ar, R, R², R³ and g are defined as in claim 2; X² is selectedfrom the group consisting of NO₂ and —NH₂, optionally protected with achemical protecting group; or a salt of such a compound.
 5. A compoundaccording to claim 4 wherein Ar is optionally substituted phenyl; or asalt of such a compound.
 6. A compound according to claim 1 wherein R ishydrogen or (C₁-C₆)alkyl.
 7. A compound according to claim 6 wherein Aris optionally substituted phenyl.
 8. A compound according to claim 7 ofthe formula I′:

wherein: each R³ is independently selected from —(C₁-C₆)alkyl; and Q isselected from the group consisting of —H, —(C₁-C₆)alkoxy, halogen,—(C₁-C₆)alkyl and —NR⁴ ₂; or a salt of such a compound.
 9. A compoundaccording to claim 4 of formula IIIa′:

wherein: X², R, R² and g are defined as in claim 3; each R³ isindependently selected from —(C₁-C₆)alkyl; and Q is selected from thegroup consisting of —H, —(C₁-C₆)alkoxy, halogen, —(C₁-C₆)alkyl and —NR⁴₂; or a salt of such a compound.
 10. A compound according to claim 9wherein Q is —(C₁-C₆)alkoxy; or a salt of such a compound.
 11. Acompound according to claim 10 wherein Q is —OCH₃; or a salt of such acompound.
 12. A compound according to claim 11 wherein R³ is —CH₃; or asalt of such a compound.
 13. A compound according to claim 12 whereinsaid compound is(E)-2,4,6-trimethoxystyryl-4-methoxy-3-aminophenylsulfonamide; or a saltof such a compound.
 14. A compound of formula IIa:

wherein: Ar is selected from the group consisting of substituted andunsubstituted aryl, and substituted and unsubstituted heteroaryl; g is 0or 1; R is selected from the group consisting of —H, (C₁-C₆)alkyl,(C₁-C₆)alkoxy, (C₃-C₆)alkenyl, (C₂-C₆)heteroalkyl, (C₃-C₆)heteroalkenyl,(C₂-C₆)hydroxyalkyl, substituted aryl, unsubstituted aryl, substitutedheterocyclic, unsubstituted heterocyclic, substituted aryl(C₁-C₃)alkyl,unsubstituted aryl(C₁-C₃)alkyl, substituted heterocyclic(C₁-C₃)alkyl andunsubstituted heterocyclic(C₁-C₃)alkyl; R³ is independently selectedfrom C₁-C₆)alkyl; X² is selected from the group consisting of NO₂ and—NH₂, optionally protected with a chemical protecting group; or a saltof such a compound.
 15. A compound according to claim 14 which is(E)-2,4,6-trimethoxy-styryl-4-methoxy-3-nitrophenylsulfonamide; or asalt of such a compound.
 16. A compound according to claim 1, wherein: Xis

y is 1; M is —(CH₂)_(a)—V—(CH₂)_(b)—; V is —C(═O)—; or a salt of such acompound.
 17. A compound according to claim 16, wherein Ar is optionallysubstituted phenyl.
 18. A compound according to claim 17, having theformula IV:

wherein: each R³ is independently selected from —(C₁-C₆)alkyl; and Q isselected from the group consisting of —H, —(C₁-C₆)alkoxy, halogen,—(C₁-C₆)alkyl and —NR⁴ ₂; or a salt of such a compound.
 19. A compoundaccording to claim 18, wherein g is 0; or a salt of such a compound. 20.A compound according to claim 19 selected from the group consisting of:(E)-2,4,6-trimethoxystyryl-N-[(3-carboxyacetamido)-4-methoxyphenyl]-sulfonamide;(E)-2,4,6-trimethoxystyryl-N-[3-(3,5,dinitrobenzamido)4-methoxy-phenyl]-sulfonamide;(E)-2,4,6-trimethoxystyryl-N-[3-(3,5,diaminobenzamido)-4-methoxy-phenyl]-sulfonamide;(E)-2,4,6-trimethoxystyryl-N-[(3-chloroacetamido)-4-methoxyphenyl]-sulfonamide;(E)-2,4,6-trimethoxystyryl-N-[3-(4-methylpiperazinyl)acetamido-4-methoxy-phenyl]sulfonamide;(E)-2,4,6-trimethoxystyryl-N-[(3-benzamido)-4-methoxyphenyl]-sulfonamide;(E)-2,4,6-trimethoxystyryl-N-3[(4-nitrobenzamido)-4-methoxyphenyl]-sulfonamide;(E)-2,4,6-trimethoxystyryl-N-3[(4-aminobenzamido)-4-methoxyphenyl]-sulfonamide;(E)-2,4,6-trimethoxystyryl-N-[(3-acetamido)-4-methoxyphenyl]-sulfonamide;(E)-2,4,6-trimethoxystyryl-N-[(3-hydroxyacetamido)-4-methoxyphenyl)]-sulfonamide;and(E)-2,4,6-trimethoxystyryl-N-[(3-N,N-dimethylacetamido)-4-methoxyphenyl]-sulfonamide;or a salt of such a compound.
 21. A compound according to claim 1wherein: X is

y is 1; and M is -Z-; or a salt of such a compound.
 22. A compoundaccording to claim 21, wherein Ar is optionally substituted phenyl. 23.A compound according to claim 22, having the formula V:

wherein: each R³ is independently selected from —(C₁-C₆)alkyl; and Q isselected from the group consisting of —H, —(C₁-C₆)alkoxy, halogen,—(C₁-C₆)alkyl and —NR⁴ ₂; or a salt of such a compound.
 24. A compoundaccording to claim 23, wherein g is 0; or a salt of such a compound. 25.A compound according to claim 24 selected from the group consisting of:(E)-2,4,6-trimethoxystyryl-N-[(3-amino)4-methoxyphenyl]sulfonamide-L-lysineamide;(E)-2,4,6-trimethoxystyryl-N-[(3-amino)-4-methoxyphenyl]sulfonamide-L-serineamide;(E2,4,6-trimethoxystyryl-N-[(3-amino)-4-methoxyphenyl]sulfonamide-D-serineamide;or a salt of such a compound.
 26. A compound according to claim 1,wherein: X is

y is 1; M is —(CH₂)_(a)—V—(CH₂)_(b)—; and V is —SO₂—; or a salt of sucha compound.
 27. A compound according to claim 26, wherein Ar isoptionally substituted phenyl; or a salt of such a compound.
 28. Acompound according to claim 27, having the formula VI:

wherein: each R³ is independently selected from —(C₁-C₆)alkyl; and Q isselected from the group consisting of —H, C₁-C₆)alkoxy, halogen,—(C₁-C₆)alkyl and —NR⁴ ₂; or a salt of such a compound.
 29. A compoundaccording to claim 28, wherein g is 0; or a salt of such a compound. 30.A compound according to claim 29 selected from the group consisting of:(E)-2,4,6-trimethoxystyryl-N-[(3-carboxymethylsulfamyl)-4-methoxy-phenyl]sulfonamide;(E)-2,4,6-trimethoxystyryl-N-[3-(3,5-dinitrobenzenesulfamyl)-4-methoxy-phenyl]sulfonamide;(E)-2,4,6-trimethoxystyryl-N-[3-(3,5-diaminobenzenesulfamyl)-4-methoxy-phenyl]sulfonamide;or a salt of such a compound.
 31. A compound according to claim 1wherein: X is

y is 0; R¹ is —C(—NH)—NR³ ₂; or a salt of such a compound.
 32. Acompound according to claim 31 wherein Ar is optionally substitutedphenyl; or a salt of such a compound.
 33. A compound according to claim32 having the formula VII:

wherein: each R³ is independently selected from —(C₁-C₆)alkyl; and Q isselected from the group consisting of —H, —(C₁-C₆)alkoxy, halogen,—(C₁-C₆)alkyl and —NR⁴ ₂; or a salt of such a compound.
 34. A compoundaccording to claim 33, wherein g is 0, or a salt of such a compound. 35.A compound according to claim 34 wherein said compound is(E)-2,4,6-trimethoxystyryl-N-[(3-guanidino)-4-methoxyphenyl]sulfonamide;or a salt of such a compound.
 36. A compound according to claim 1wherein: X is

y is 1; and M is C₁-C₆)alkylene-; or a salt of such a compound.
 37. Acompound according to claim 36 wherein Ar is optionally substitutedphenyl; or a salt of such a compound.
 38. A compound according to claim37 having the formula VIII:

wherein: each R³ is independently selected from —(C₁-C₆)alkyl; and Q isselected from the group consisting of —H, —(C₁-C₆)alkoxy, halogen,—(C₁-C₆)alkyl and —NR⁴ ₂; or a salt of such a compound.
 39. A compoundaccording to claim 38, wherein g is 0; or a salt of such a compound. 40.A compound according to claim 39 selected from the group consisting of:(E)-2,4,6-trimethoxystyryl-N-[(3-carboxymethylamino)4-methoxy-phenyl]-sulfonamide;(E)-2,4,6-trimethoxystyryl-N-[(3-N-methylamino)-4-methoxyphenyl]-sulfonamide;or a salt of such a compound.
 41. A compound according to claim 1 havingthe formula IX:

wherein: each R³ is independently selected from —(C₁-C₆)alkyl; and Q isselected from the group consisting of —H, —(C₁-C₆)alkoxy, halogen,—(C₁-C₆)alkyl and —NR⁴ ₂; or a salt of such a compound.
 42. A compoundaccording to claim 41, wherein g is 0; or a salt of such a compound. 43.A compound according to claim 42 wherein said compound is(E)-2,4,6-trimethoxystyryl-N-3[(4-nitrophenylimino)-4-methoxyphenyl]-sulfonamide; or a salt of such acompound.
 44. A compound of formula I according to claim 1 wherein: X is

y is 1; M is —(CH₂)_(a)—V—(CH₂)_(b)—; and V is C═O)NR⁴—; or a salt ofsuch a compound.
 45. A compound according to claim 44, wherein Ar isoptionally substituted phenyl; or a salt of such a compound.
 46. Acompound according to claim 45 having the formula X:

wherein: each R³ is independently selected from —(C₁-C₆)alkyl; and Q isselected from the group consisting of —H, —(C₁-C₆)alkoxy, halogen,—(C₁-C₆)alkyl and —NR⁴ ₂; or a salt of such a compound.
 47. A compoundaccording to claim 46, wherein g is 0; or a salt of such a compound. 48.A compound according to claim 47 which is(E)-2,4,6-trimethoxystyryl-N-[(3-ureido)-4-methoxyphenyl]sulfonamide, ora salt of such a compound.
 49. A process for preparing a compound ofclaim 1 comprising: (1) coupling a compound of formula IIIa:

wherein: X² is selected from the group consisting of —NO₂ and —NH₂,optionally protected with a chemical protecting group; or a salt of sucha compound; with a compound of formula XIR¹-A  XI wherein: R¹, R⁴, R⁵, R⁶, and R⁷ are defined as in claim 1; andA is a moiety containing an electrophilic reactive center, said moietyselected from the group consisting of: (a) an alkyl moiety having aleaving group; (b) an aryl halide or aryl pseudo halide; (c) acarboxylic acid activated with a leaving group; (d) a sulfonic acidactivated with a leaving group; (e) a carbamic acid moiety activatedwith a leaving group; (f) a cyanate moiety; (g) an aldehyde or ketonemoiety, or a hydrate thereof or a ketal or acetal thereof; (h) acarboxylic acid moiety and an amide coupling reagent; or (i) theintermediate product of a thiourea moiety and 2-chloro-1-methylpyridinium iodide; to form a compound of formula Ia:

(2) optionally (a) when —X² is —NH₂ protected with a protecting group,removing said protecting group from —X² to yield a compound of formulaIb; or (b) when —X² is —NO₂, chemically reducing said —NO₂ to —NH₂, toform a compound of formula Ib:

(3) optionally coupling said compound of formula Ib or a salt of such acompound: with a compound of formula XI:R¹-A  XI wherein one or more functional groups comprising R¹ areoptionally protected by chemical protecting groups; and wherein A is amoiety containing an electrophilic reactive center as defined above; and(4) optionally removing said protecting groups protectingfunctionalities on R¹ to form a compound of formula I:

or a salt of such a compound.
 50. A process for preparing a compoundaccording to claim 5 of the formula IIIa:

wherein: Ar is selected from the group consisting of substituted andunsubstituted aryl, and substituted and unsubstituted heteroaryl; X² isselected from the group consisting of —NO₂ and —NH₂, optionallyprotected with a chemical protecting group. g is 0 or 1; R is selectedfrom the group consisting of —H, (C₁-C₆)alkyl, (C₁-C₆)alkoxy,(C₃-C₆)alkenyl, (C₂-C₆)heteroalkyl, (C₃-C₆)heteroalkenyl,(C₂-C₆)hydroxyalkyl, substituted aryl, unsubstituted aryl, substitutedheterocyclic, unsubstituted heterocyclic, substituted aryl(C₁-C₃)alkyl,unsubstituted aryl(C₁-C₃)alkyl, substituted heterocyclic(C₁-C₃)alkyl andunsubstituted heterocyclic(C₁-C₃)alkyl; R³ is independently selectedfrom —(C₁-C₆)alkyl; or a salt of such a compound; comprising (1)chemically reducing a compound according to formula IIa:

wherein Ar is selected from the group consisting of substituted andunsubstituted aryl, and substituted and unsubstituted heteroaryl; X² isselected from the group consisting of —NO₂ and —NH₂, optionallyprotected with a chemical protecting group. g is 0 or 1; R is selectedfrom the group consisting of —H, (C₁-C₆)alkyl, (C₁-C₆)alkoxy,(C₃-C₆)alkenyl, (C₂-C₆)heteroalkyl, (C₃-C₆)heteroalkenyl,(C₂-C₆)hydroxyalkyl, substituted aryl, unsubstituted aryl, substitutedheterocyclic, unsubstituted heterocyclic, substituted aryl(C₁-C₃)alkyl,unsubstituted aryl(C₁-C₃)alkyl, substituted heterocyclic(C₁-C₃)alkyl andunsubstituted heterocyclic(C₁-C₃)alkyl; R³ is independently selectedfrom —(C₁-C₆)alkyl; or a salt of such a compound; and (2) alkylating theaniline reduction product of step 1; to form a compound of formula IIIa.51. A process according to claim 50 wherein the compound of formula IIais prepared by condensing a compound of formula D:

wherein: R is selected from the group consisting of —H, (C₁-C₆)alkyl,(C₁-C₆)alkoxy, (C₃-C₆)alkenyl, (C₂-C₆)heteroalkyl, (C₃-C₆)heteroalkenyl,(C₂-C₆)hydroxyalkyl, substituted aryl, unsubstituted aryl, substitutedheterocyclic, unsubstituted heterocyclic, substituted aryl(C₁-C₃)alkyl,unsubstituted aryl(C₁-C₃)alkyl, substituted heterocyclic(C₁-C₃)alkyl andunsubstituted heterocyclic(C₁-C₃)alkyl; R³ is independently selectedfrom —(C₁-C₆)alkyl; and g is 0 or 1; and X² is selected from the groupconsisting of —NO₂ and —NH₂, optionally protected with a chemicalprotecting group; with a compound of formula E:

wherein: each R³ is independently selected from —(C₁-C₆)alkyl; and eachR⁴ is independently selected from the group consisting of —H, and—(C₁-C₆)alkyl; and Q is selected from the group consisting of —H,—(C₁-C₆)alkoxy, halogen, C₁-C₆)alkyl and —NR⁴²; and salts thereof; toform said compound of formula IIa; or a salt of such a compound.
 52. Aprocess for preparing a compound of claim 1 comprising: (1) coupling acompound of formula C′:

wherein: X² is —NH₂, optionally protected with a chemical protectinggroup. g is 0 or 1; R³ is independently selected from —(C₁-C₆)alkyl; ora salt of such a compound; with a compound of formula XIR¹-A  XI wherein: R¹ is selected from the group consisting of —H,unsubstituted aryl, substituted aryl, substituted heterocyclic,unsubstituted heterocyclic, —CO₂R⁵, —C(═O)NR⁴ ₂, —CHR⁶R⁷, —C(═NH)—NR⁴ ₂and a monovalent peptidyl moiety with a molecular weight of less than1000; each R⁴ is independently selected from the group consisting of —H,and (C₁-C₆)alkyl; each R⁵ is independently selected from the groupconsisting of —H, —(C₁-C₆)alkyl and —(C₁-C₆)acyl; R⁶ is selected fromthe group consisting of —H, —(C₁-C₆)alkyl, —CO₂R⁵, —C(═O)R⁷, —OH, —SR⁴,—(C₁-C₃)alkoxy, —(C₁-C₃)alkylthio, guanidino, —NR⁴ ₂, phenyl,substituted phenyl, heterocyclic, substituted heterocyclic and halogen;R⁷ is selected from the group consisting of —H, halogen, —(C₁-C₆)alkyl,—NR⁴ ₂ and heterocycles containing two nitrogen atoms; wherein thesubstituents for the substituted aryl and substituted heterocyclicgroups comprising or included within R¹, R⁶ and R⁷, are independentlyselected from the group consisting of halogen, (C₁-C₆)alkyl,(C₁-C₆)alkoxy, —NO₂, —C≡N, —CO₂R⁵, —C(═O)O(C₁-C₃)alkyl, —OH,—(C₂-C₆)—OH, phosphonato, —NR⁴ ₂, —NHC(═O)(C₁-C₆)alkyl, sulfamyl,—OC(═O)(C₁-C₃)alkyl, —O(C₂-C₆)—N((C₁-C₆)alkyl)₂ and —CF₃; and whereinone or more functional groups comprising R¹ are optionally protected bychemical protecting groups; and wherein A is a moiety containing anelectrophilic reactive center, said moiety selected from the groupconsisting of: (a) an alkyl moiety having a leaving group; (b) an arylhalide or aryl pseudo halide; (c) a carboxylic acid activated with aleaving group; (d) a sulfonic acid activated with a leaving group; (e) acarbamic acid moiety activated with a leaving group; (f) a cyanatemoiety; (g) an aldehyde or ketone moiety, or a hydrate thereof or aketal or acetal thereof; (h) a carboxylic acid moiety and an amidecoupling reagent; or (i) the intermediate product of a thiourea moietyand 2-chloro-1-methyl pyridinium iodide; to form a compound of formulaIa′:

(2) optionally removing said protecting group from X² to yield acompound of formula Ib′;

(3) optionally coupling said compound of formula Ib′ or a salt of such acompound: with a compound of formula XI:R¹-A  XI wherein one or more functional groups comprising R¹ areoptionally protected by chemical protecting groups; and wherein A is amoiety containing an electrophilic reactive center as defined above; toform a compound of formula Ic′:

(4) chemically reducing said compound of formula Ic′ to give a compoundof formula Id′:

(5) optionally reacting said compound of formula Id′ with: (a) analdehyde or ketone under reductive amination conditions; or (b)alkylating the aniline nitrogen of Id′ with an alkyl moiety having aleaving group. To form a compound of formula Ie′:

(6) reacting said compound of formula Ie′ with an ester ofchlorosulfonylacetic acid;

(7) hydrolysing said compound of formula If′, to give a compound offormula Ig′:

(8) reacting said compound of formula Ig′ with an aryl aldehyde, H:

and (9) optionally removing said protecting groups protectingfunctionalities on R¹ to form a compound of formula I:


53. A process for producing a compound according to claim 18 having theformula IV, comprising, (1) coupling a compound of formula IIIa:

wherein: Ar is selected from the group consisting of substituted andunsubstituted aryl, and substituted and unsubstituted heteroaryl; X² isselected from the group consisting of —NO₂ and —NH₂, optionallyprotected with a chemical protecting group. g is 0 or 1; R is selectedfrom the group consisting of —H, (C₁-C₆)alkyl, (C₁-C₆)alkoxy,(C₃-C₆)alkenyl, (C₂-C₆)heteroalkyl, (C₃-C₆)heteroalkenyl,(C₂-C₆)hydroxyalkyl, substituted aryl, unsubstituted aryl, substitutedheterocyclic, unsubstituted heterocyclic, substituted aryl(C₁-C₃)alkyl,unsubstituted aryl(C₁-C₃)alkyl, substituted heterocyclic(C₁-C₃)alkyl andunsubstituted heterocyclic(C₁-C₃)alkyl; R³ is independently selectedfrom —(C I—C₆)alkyl; or a salt of such a compound; with a compound offormula XII:R¹-A¹  XII wherein: R¹ is selected from the group consisting of —H,unsubstituted aryl, substituted aryl, substituted heterocyclic,unsubstituted heterocyclic, —CO₂R⁵, —C(═O)NR⁴ ₂, —CHR⁶R⁷, —C(═NH)—NR⁴ ₂and a monovalent peptidyl moiety with a molecular weight of less than1000; each R⁴ is independently selected from the group consisting of —H,and —(C₁-C₆)alkyl; each R⁵ is independently selected from the groupconsisting of —H, —(C₁-C₆)alkyl and —(C₁-C₆)acyl; R⁶ is selected fromthe group consisting of —H, —(C₁-C₆)alkyl, —CO₂R⁵, —C(═O)R⁷, —OH, —SR⁴,—(C₁-C₃)alkoxy, —(C₁-C₃)alkylthio, guanidino, —NR⁴ ₂, phenyl,substituted phenyl, heterocyclic, substituted heterocyclic and halogen;R⁷ is selected from the group consisting of —H, halogen, —(C₁-C₆)alkyl,—NR⁴ ₂ and heterocycles containing two nitrogen atoms; wherein thesubstituents for the substituted aryl and substituted heterocyclicgroups comprising or included within R¹, R⁶ and R⁷, are independentlyselected from the group consisting of halogen, (C₁-C₆)alkyl,(C₁-C₆)alkoxy, —NO₂, —C≡N, —CO₂R⁵, —C(═O)O(C₁-C₃)alkyl, —OH,—(C₂-C₆)—OH, phosphonato, —NR⁴ ₂, —NHC(═O)(C₁-C₆)alkyl, sulfamyl,—OC(═O)(C₁-C₃)alkyl, —O(C₂-C₆)—N((C₁-C₆)alkyl)₂ and —CF₃; and whereinone or more functional groups comprising R¹ are optionally protected bychemical protecting groups; and A¹ is a carboxylic acid moietycontaining a leaving group to form a compound of formula IVa:

(2) optionally: (a) when —X² is —NH₂ protected with a protecting group,removing said protecting group from —X² to yield a compound of formulaIVb; or (b) when —X² is —NO₂, chemically reducing said —NO₂ to —NH₂ toform a compound of formula IVb:

(3) optionally coupling said compound of formula IVb or a salt of such acompound, with a compound of formula XI:R¹-A  XI wherein one or more functional groups comprising R¹ areoptionally protected by chemical protecting groups; and wherein A is amoiety containing an electrophilic reactive center as defined above; and(4) optionally removing said protecting groups protectingfunctionalities on R¹ to form said compound of formula IV or a salt ofsuch a compound.
 54. A process for producing a compound according toclaim 23 having the formula V:

comprising: (1) reacting a compound of formula IIIa

wherein: Ar is selected from the group consisting of substituted andunsubstituted aryl, and substituted and unsubstituted heteroaryl; X² isselected from the group consisting of —NO₂ and —NH₂, optionallyprotected with a chemical protecting group. g is 0 or 1; R is selectedfrom the group consisting of —H, (C₁-C₆)alkyl, (C₁-C₆)alkoxy,(C₃-C₆)alkenyl, (C₂-C₆)heteroalkyl, (C₃-C₆)heteroalkenyl,(C₂-C₆)hydroxyalkyl, substituted aryl, unsubstituted aryl, substitutedheterocyclic, unsubstituted heterocyclic, substituted aryl(C₁-C₃)alkyl,unsubstituted aryl(C₁-C₃)alkyl, substituted heterocyclic(C₁-C₃)alkyl andunsubstituted heterocyclic(C₁-C₃)alkyl; R³ is independently selectedfrom —(C₁-C₆)alkyl; or a salt of such a compound; with (a) a compound offormula XIII:R¹-A²  XIII wherein R^(a) is selected from the group consisting of —H,—CH₃, —(CH₂)₃—NH—C(NH₂)(═NH), —CH₂C(═O)NH₂, —CH₂COOH, —CH₂SH,—(CH₂)₂C(═O)—NH₂, —(CH₂)₂COOH, —CH₂-(2-imidazolyl), —CH(CH₃)—CH₂—CH₃,—CH₂CH(CH₃)₂, —(CH₂)₄—NH₂, —(CH₂)₂—S—CH₃, phenyl, CH₂-phenyl, —CH₂—OH,—CH(OH)—CH₃, —CH₂-(3-indolyl), —CH₂-(4-hydroxyphenyl), —CH(CH₃)₂ and—CH₂—CH₃; and includes compounds wherein R^(a) and R¹ combine to form a5-, 6 or 7-membered heterocyclic ring; R¹ is selected from the groupconsisting of —H, unsubstituted aryl, substituted aryl, substitutedheterocyclic, unsubstituted heterocyclic, —CO₂R⁵, —C(—O)NR⁴ ₂, —CHR⁶R⁷,—C(═NH)—NR⁴ ₂ and a monovalent peptidyl moiety with a molecular weightof less than 1000 and coupled through the peptide's carboxy terminus orthrough a sidechain carboxyl group to form a carboxamide bond; each R⁴is independently selected from the group consisting of —H, and—(C₁-C₆)alkyl; R¹ is selected from the group consisting of —H,—(C₁-C₆)alkyl and —(C₁-C₆)acyl; R⁶ is selected from the group consistingof —H, —(C₁-C₆)alkyl, —CO₂R⁵, —C(═O)R⁷, —OH, —SR⁴, —(C—C₃)alkoxy,—(C₁-C₃)alkylthio, guanidino, —NR⁴ ₂, phenyl, substituted phenyl,heterocyclic, substituted heterocyclic and halogen; R⁷ is selected fromthe group consisting of —H, halogen, —(C₁-C₆)alkyl, —NR⁴ ₂ andheterocycles containing two nitrogen atoms; wherein the substituents forthe substituted aryl and substituted heterocyclic groups comprising orincluded within R¹, R^(a), R⁶ and R⁷, are independently selected fromthe group consisting of halogen, (C₁-C₆)alkyl, (C₁-C₆)alkoxy, —NO₂,—C_═N, —CO₂R⁵, —C(═O)O(C₁-C₃)alkyl, —OH, —(C₂-C₆)—OH, phosphonato, —NR⁴₂, —NHC(═O)(C₁-C₆)alkyl, sulfamyl, —OC(═O)(C₁-C₃)alkyl,—O(C₂-C₆)—N((C₁-C₆)alkyl)₂ and —CF₃; and wherein one or more functionalgroups comprising R¹ are optionally protected by chemical protectinggroups; and (b) an amide coupling reagent; to form a compound of formulaVa:

(2) optionally: (a) when —X² is —NH₂ protected with a protecting group,removing said protecting group from —X² to yield a compound of formulaVb; or (b) when —X² is —NO₂, chemically reducing said —NO₂ to —NH₂, toform a compound of formula Vb:

(3) optionally coupling said compound of formula Vb or a salt of such acompound: with a compound of formula XI:R¹-A  XI wherein one or more functional groups comprising R¹ areoptionally protected by chemical protecting groups; and wherein A is amoiety containing an electrophilic reactive center as defined above; and(4) optionally removing said protecting groups protectingfunctionalities on R¹ to form said compound of formula V; or a salt ofsuch a compound.
 55. A process for producing a compound according toclaim 28 having the formula VI:

comprising, (1) coupling a compound of formula IIIa:

wherein: Ar is selected from the group consisting of substituted andunsubstituted aryl, and substituted and unsubstituted heteroaryl; X² isselected from the group consisting of —NO₂ and —NH₂, optionallyprotected with a chemical protecting group. g is 0 or 1; R is selectedfrom the group consisting of —H, (C₁-C₆)alkyl, (C₁-C₆)alkoxy,(C₃-C₆)alkenyl, (C₂-C₆)heteroalkyl, (C₃-C₆)heteroalkenyl,(C₂-C₆)hydroxyalkyl, substituted aryl, unsubstituted aryl, substitutedheterocyclic, unsubstituted heterocyclic, substituted aryl(C₁-C₃)alkyl,unsubstituted aryl(C₁-C₃)alkyl, substituted heterocyclic(C₁-C₃)alkyl andunsubstituted heterocyclic(C₁-C₃)alkyl; R³ is independently selectedfrom —(C₁-C₆)alkyl; each R⁴ is independently selected from the groupconsisting of —H, and —(C₁-C₆)alkyl; or a salt of such a compound; witha compound of formula XIV:R¹-A³  XIV wherein: R¹ is selected from the group consisting of —H,unsubstituted aryl, substituted aryl, substituted heterocyclic,unsubstituted heterocyclic, —CO₂R⁵, —C(═O)NR⁴ ₂, —CHR⁶R⁷, —C(═NH)—NR⁴ ₂and a monovalent peptidyl moiety with a molecular weight of less than1000; each R⁴ is independently selected from the group consisting of —H,and —(C₁-C₆)alkyl; each R⁵ is independently selected from the groupconsisting of —H, (C₁-C₆)alkyl and —(C₁-C₆)acyl; R⁶ is selected from thegroup consisting of —H, —(C₁-C₆)alkyl, —CO₂R⁵, —C(═O)R⁷, —OH, —SR,—(C₁-C₃)alkoxy, —(C₁-C₃)alkylthio, guanidino, —NR⁴ ₂, phenyl,substituted phenyl, heterocyclic, substituted heterocyclic and halogen;R⁷ is selected from the group consisting of —H, halogen, —(C₁-C₆)alkyl,—NR⁴ ₂ and heterocycles containing two nitrogen atoms; wherein thesubstituents for the substituted aryl and substituted heterocyclicgroups comprising or included within R¹, R⁶ and R⁷, are independentlyselected from the group consisting of halogen, (C₁-C₆)alkyl,(C₁-C₆)alkoxy, —NO₂, —C≡N, —CO₂R⁵, —C(═O)O(C₁-C₃)alkyl, —OH,—(C₂-C₆)—OH, phosphonato, —NR⁴ ₂, —NHC(═O)(C₁-C₆)alkyl, sulfamyl,—OC(═O)(C₁-C₃)alkyl, —O(C₂-C₆)—N((C₁-C₆)alkyl)₂ and —CF₃; and whereinone or more functional groups comprising R¹ are optionally protected bychemical protecting groups; and A³ is a sulfonyl chloride moiety; toform a compound of formula VIa:

(2) optionally: (a) when —X² is —NH₂ protected with a protecting group,removing said protecting group from —X² to yield a compound of formulaVIb; or (b) when —X² is —NO₂, chemically reducing said —NO₂ to —NH₂, toform a compound of formula VIb:

(3) optionally coupling said compound of formula VIb or a salt of such acompound: with a compound of formula XI:R¹-A  XI wherein one or more functional groups comprising R¹ areoptionally protected by chemical protecting groups; and wherein A is amoiety containing an electrophilic reactive center as defined above; and(4) optionally removing said protecting groups protectingfunctionalities on R¹ to form said compound of formula VI:
 56. A processfor producing a compound according to claim 33 having the formula VII:

comprising, (1) coupling a compound of formula IIIa:

wherein: Ar is selected from the group consisting of substituted andunsubstituted aryl, and substituted and unsubstituted heteroaryl; X² isselected from the group consisting of —NO₂ and —NH₂, optionallyprotected with a chemical protecting group. g is 0 or 1; R is selectedfrom the group consisting of —H. (C₁-C₆)alkyl, (C₁-C₆)alkoxy,(C₃-C₆)alkenyl, (C₂-C₆)heteroalkyl, (C₃-C₆)heteroalkenyl,(C₂-C₆)hydroxyalkyl, substituted aryl, unsubstituted aryl, substitutedheterocyclic, unsubstituted heterocyclic, substituted aryl(C₁-C₃)alkyl,unsubstituted aryl(C₁-C₃)alkyl, substituted heterocyclic(C₁-C₃)alkyl andunsubstituted heterocyclic(C₁-C₃)alkyl; R³ is independently selectedfrom —(C₁-C₆)alkyl; or a salt of such a compound; with a compound offormula XV:R¹-A⁴  XV wherein one or more functional groups comprising R¹ areoptionally protected by chemical protecting groups; and wherein A⁴ ismoiety which is a reactive intermediate product of a substitutedthiourea and 2-chloro-1-methylpyridinium iodide; to form a compound offormula VIIa:

(2) optionally: (a) when —X² is —NH₂ protected with a protecting group,removing said protecting group from —X² to yield a compound of formulaVIIb; or (b) when —X² is —NO₂, chemically reducing said —NO₂ to —NH₂, toform a compound of formula VIIb:

(3) optionally coupling said compound of formula VIIb or a salt of sucha compound: with a compound of formula XI:R¹-A  XI wherein one or more functional groups comprising R¹ areoptionally protected by chemical protecting groups; and wherein A is amoiety containing an electrophilic reactive center as defined above; and(4) optionally removing said protecting groups protectingfunctionalities on R¹ to form said compound of formula VII; or a salt ofsuch a compound.
 57. A process for producing a compound according toclaim 38 having the formula VIII:

comprising: (1) coupling a compound of formula IIIa:

wherein: Ar is selected from the group consisting of substituted andunsubstituted aryl, and substituted and unsubstituted heteroaryl; X² isselected from the group consisting of —NO₂ and —NH₂, optionallyprotected with a chemical protecting group. g is 0 or 1; R is selectedfrom the group consisting of —H. (C₁-C₆)alkyl, (C₁-C₆)alkoxy,(C₃-C₆)alkenyl, (C₂-C₆)heteroalkyl, (C₃-C₆)heteroalkenyl,(C₂-C₆)hydroxyalkyl, substituted aryl, unsubstituted aryl, substitutedheterocyclic, unsubstituted heterocyclic, substituted aryl(C₁-C₃)alkyl,unsubstituted aryl(C₁-C₃)alkyl, substituted heterocyclic(C₁-C₃)alkyl andunsubstituted heterocyclic(C₁-C₃)alkyl; R³ is independently selectedfrom —(C₁-C₆)alkyl; or a salt of such a compound; with a compound offormula XVIR¹-A⁵  XVI wherein: R¹ is selected from the group consisting of —H,unsubstituted aryl, substituted aryl, substituted heterocyclic,unsubstituted heterocyclic, —CO₂R⁵, —C(═O)NR⁴ ₂, —CHR⁶R⁷, —C(═NH)—NR⁴ ₂and a monovalent peptidyl moiety with a molecular weight of less than1000; each R⁴ is independently selected from the group consisting of —H,and —(C₁-C₆)alkyl; each R⁵ is independently selected from the groupconsisting of —H, —(C₁-C₆)alkyl and —(C₁-C₆)acyl; R⁶ is selected fromthe group consisting of —H, —(C₁-C₆)alkyl, —CO₂R⁵, —C(═O)R⁷, —OH, —SR⁴,—(C₁-C₃)alkoxy, —(C₁-C₃)alkylthio, guanidino, —NR⁴ ₂, phenyl,substituted phenyl, heterocyclic, substituted heterocyclic and halogen;R⁷ is selected from the group consisting of —H, halogen, —(C₁-C₆)alkyl,—NR⁴ ₂ and heterocycles containing two nitrogen atoms; wherein thesubstituents for the substituted aryl and substituted heterocyclicgroups comprising or included within R¹, R⁶ and R⁷, are independentlyselected from the group consisting of halogen, (C₁-C₆)alkyl,(C₁-C₆)alkoxy, —NO₂, —C—N, —CO₂R⁵, —C(═O)O(C₁-C₃)alkyl, —OH,—(C₂-C₆)—OH, phosphonato, —NR⁴ ₂, —NHC(═O)(C₁-C₆)alkyl, sulfamyl,—OC(═O)(C₁-C₃)alkyl, —O(C₂-C₆)—N((C₁-C₆)alkyl)₂ and —CF₃; and whereinone or more functional groups comprising R¹ are optionally protected bychemical protecting groups; and wherein A⁵ is an alkyl moiety containinga leaving group; to form a compound of formula VIIa:

(2) optionally: (a) when —X² is —NH₂ protected with a protecting group,removing said protecting group from —X² to yield a compound of formulaVIIIb; or (b) when —X² is —NO₂, chemically reducing said —NO₂ to —NH₂,to form a compound of formula VIIIb:

(3) optionally coupling said compound of formula VIIIb or a salt of sucha compound: with a compound of formula XI:R¹-A  XI wherein one or more functional groups comprising R¹ areoptionally protected by chemical protecting groups; and wherein A is amoiety containing an electrophilic reactive center as defined above; and(4) optionally removing said protecting groups protectingfunctionalities on R¹ to form said compound of formula VIII; or a saltof such a compound.
 58. A process for producing a compound according toclaim 41 having the formula IX:

comprising; (1) coupling a compound of formula IIIa:

wherein: Ar is selected from the group consisting of substituted andunsubstituted aryl, and substituted and unsubstituted heteroaryl; X² isselected from the group consisting of —NO₂ and —NH₂, optionallyprotected with a chemical protecting group. g is 0 or 1; R is selectedfrom the group consisting of —H, (C₁-C₆)alkyl, (C₁-C₆)alkoxy,(C₃-C₆)alkenyl, (C₂-C₆)heteroalkyl, (C₃-C₆)heteroalkenyl,(C₂-C₆)hydroxyalkyl, substituted aryl, unsubstituted aryl, substitutedheterocyclic, unsubstituted heterocyclic, substituted aryl(C₁-C₃)alkyl,unsubstituted aryl(C₁-C₃)alkyl, substituted heterocyclic(C₁-C₃)alkyl andunsubstituted heterocyclic(C₁-C₃)alkyl; R² is —H; R³ is independentlyselected from —(C₁-C₆)alkyl; or a salt of such a compound; with acompound of formula XVIIR¹-A⁶  XVII wherein: R¹ is selected from the group consisting of —H,unsubstituted aryl, substituted aryl, substituted heterocyclic,unsubstituted heterocyclic, —CO₂R⁵, —C(═O)NR⁴ ₂, —CHR⁶R⁷, —C(═NH)—NR⁴ ₂and a monovalent peptidyl moiety with a molecular weight of less than1000; each R⁴ is independently selected from the group consisting of —H,and —(C₁-C₆)alkyl; each R⁵ is independently selected from the groupconsisting of —H, —(C₁-C₆)alkyl and —(C₁-C₆)acyl; R⁶ is selected fromthe group consisting of —H, —(C₁-C₆)alkyl, —CO₂R⁵, —C(═O)R⁷, —OH, —SR⁴,—(C₁-C₃)alkoxy, —(C₁-C₃)alkylthio, guanidino, —NR⁴ ₂, phenyl,substituted phenyl, heterocyclic, substituted heterocyclic and halogen;R⁷ is selected from the group consisting of —H, halogen, —(C₁-C₆)alkyl,—NR⁴ ₂ and heterocycles containing two nitrogen atoms; wherein thesubstituents for the substituted aryl and substituted heterocyclicgroups comprising or included within R¹, R⁶ and R⁷, are independentlyselected from the group consisting of halogen, (C₁-C₆)alkyl,(C₁-C₆)alkoxy, —NO₂, —C═N, —CO₂R⁵, —C(═O)O(C₁-C₃)alkyl, —OH,—(C₂-C₆)—OH, phosphonato, —NR⁴ ₂, —NHC(═O)(C₁-C₆)alkyl, sulfamyl,—OC(═O)(C₁-C₃)alkyl, —O(C₂-C₆)—N((C₁-C₆)alkyl)₂ and —CF₃; and whereinone or more functional groups comprising R¹ are optionally protected bychemical protecting groups; and wherein A⁶ comprises an aldehyde orketone moiety, or a hydrate thereof or a ketal or acetal thereof; toform a compound of formula IXa:

(2) optionally: (a) when —X² is —NH₂ protected with a protecting group,removing said protecting group from —X² to yield a compound of formulaIXb; or (b) when —X² is —NO₂, chemically reducing said —NO₂ to —NH₂, toform a compound of formula IXb:

(3) optionally coupling said compound of formula IXb or a salt of such acompound: with a compound of formula AU:R¹-A  XI wherein one or more functional groups comprising R¹ areoptionally protected by chemical protecting groups; and wherein A is amoiety containing an electrophilic reactive center as described above;and (4) optionally removing said protecting groups protectingfunctionalities on R¹ to form said compound of formula IX; or a salt ofsuch a compound.
 59. A process for producing a compound according toclaim 46 having the formula X:

comprising; (1) coupling a compound of formula IIIa:

wherein: Ar is selected from the group consisting of substituted andunsubstituted aryl, and substituted and unsubstituted heteroaryl; X² isselected from the group consisting of —NO₂ and —NH₂, optionallyprotected with a chemical protecting group. g is 0 or 1; R is selectedfrom the group consisting of —H, (C₁-C₆)alkyl, (C₁-C₆)alkoxy,(C₃-C₆)alkenyl, (C₂-C₆)heteroalkyl, (C₃-C₆)heteroalkenyl,(C₂-C₆)hydroxyalkyl, substituted aryl, unsubstituted aryl, substitutedheterocyclic, unsubstituted heterocyclic, substituted aryl(C₁-C₃)alkyl,unsubstituted aryl(C₁-C₃)alkyl, substituted heterocyclic(C₁-C₃)alkyl andunsubstituted heterocyclic(C₁-C₃)alkyl; R³ is independently selectedfrom —(C₁-C₆)alkyl; or a salt of such a compound; with a compound offormula XVIII:R¹-A⁷  XVIII wherein: R¹ is selected from the group consisting of —H,unsubstituted aryl, substituted aryl, substituted heterocyclic,unsubstituted heterocyclic, —CO₂R⁵, —C(═O)NR⁴ ₂, —CHR⁶R⁷, —C(═NH)—NR⁴ ₂and a monovalent peptidyl moiety with a molecular weight of less than1000; each R⁴ is independently selected from the group consisting of —H,and —(C₁-C₆)alkyl; each R⁵ is independently selected from the groupconsisting of —H, —(C₁-C₆)alkyl and —(C₁-C₆)acyl; R⁶ is selected fromthe group consisting of —H, —(C₁-C₆)alkyl, —CO₂R⁵, —C(═O)R⁷, —OH, —SR⁴,—(C₁-C₃)alkoxy, —(C₁-C₃)alkylthio, guanidino, —NR⁴ ₂, phenyl,substituted phenyl, heterocyclic, substituted heterocyclic and halogen;R⁷ is selected from the group consisting of —H, halogen, —(C₁-C₆)alkyl,—NR⁴ ₂ and heterocycles containing two nitrogen atoms; wherein thesubstituents for the substituted aryl and substituted heterocyclicgroups comprising or included within R¹, R⁶ and R⁷, are independentlyselected from the group consisting of halogen, (C₁-C₆)alkyl,(C₁-C₆)alkoxy, —NO₂, —C—N, —CO₂R⁵, —C(═O)O(C₁-C₃)alkyl, —OH,—(C₂-C₆)—OH, phosphonato, —NR⁴ ₂, —NHC(═O)(C₁-C₆)alkyl, sulfamyl,—OC(═O)(C₁-C₃)alkyl, —O(C₂-C₆)—N((C₁-C₆)alkyl)₂ and —CF₃; and whereinone or more functional groups comprising R¹ are optionally protected bychemical protecting groups; and wherein: (a) if A⁷ is a cyanate moiety,then R¹ is selected from the group consisting of —H, (C₁-C₆)alkyl andaryl; and R⁴ is —H; and (b) if A⁷ is a carbamic acid moiety activatedwith a leaving group, then R¹ and R⁴ of formula X are as defined above;to form a compound of formula Xa:

(2) optionally: (a) when —X² is —NH₂ protected with a protecting group,removing said protecting group from —X² to yield a compound of formulaXb; or (b) when —X² is —NO₂, chemically reducing said —NO₂ to —NH₂; toform a compound of formula Xb:

(3) optionally coupling said compound of formula Xb or a salt of such acompound: with a compound of formula XI:R¹-A  XI wherein one or more functional groups comprising R¹ areoptionally protected by chemical protecting groups; and wherein A is amoiety containing an electrophilic reactive center as described above;and (4) optionally removing said protecting groups protectingfunctionalities on R¹ to form said compound of formula X; or a salt ofsuch a compound.
 60. A conjugate of the formula, I-L-Ab; wherein I is acompound according to claim 1; Ab is an antibody; and -L- is a singlecovalent bond or a linking group covalently linking said compound tosaid antibody.
 61. A conjugate according to claim 60 wherein saidantibody Ab is a monoclonal antibody or a monospecific polyclonalantibody.
 62. A conjugate according to claim 61 wherein said antibody Abis a tumor-specific antibody.
 63. A conjugate of the formula, III-L-Ab;wherein III is a compound according to claim 2; Ab is an antibody; and-L- is a single covalent bond or a linking group covalently linking saidcompound to said antibody.
 64. A conjugate according to claim 63 whereinsaid antibody Ab is a monoclonal antibody or a monospecific polyclonalantibody.
 65. A conjugate according to claim 64 wherein said antibody Abis a tumor-specific antibody.
 66. A conjugate of the formula, I′-L-Ab;wherein I′ is a compound according to claim 7; Ab is an antibody; and-L- is a single covalent bond or a linking group covalently linking saidcompound to said antibody.
 67. A conjugate according to claim 66 whereinsaid antibody Ab is a monoclonal antibody or a monospecific polyclonalantibody.
 68. A conjugate according to claim 67 wherein said antibody Abis a tumor-specific antibody.
 69. A pharmaceutical compositioncomprising a pharmaceutically acceptable carrier and at least onecompound according to claim 1, or a pharmaceutically acceptable salt ofsuch a compound.
 70. A pharmaceutical composition comprising apharmaceutically acceptable carrier and at least one conjugate accordingto claim 60, 63 or
 66. 71. A method of treating an individual for aproliferative disorder comprising administering to said individual aneffective amount of at least one compound according to claim 1, or apharmaceutically acceptable salt of such a compound.
 72. A methodaccording to claim 71 wherein the proliferative disorder is selectedfrom the group consisting of hemangiomatosis in newborn; secondaryprogressive multiple sclerosis; chronic progressive myelodegenerativedisease; neurofibromatosis; ganglioneuromatosis; keloid formation;Paget's Disease of the bone; fibrocystic disease, sarcoidosis; Peroniesand Duputren's fibrosis, cirrhosis, atherosclerosis and vascularrestenosis.
 73. A method according to claim 71 wherein the proliferativedisorder is cancer.
 74. A method of according to claim 73 wherein thecancer is selected from the group of cancers of the ovaries, testis,cervix, uterus, vagina, breast, prostate, lung, kidney, rectum, colon,stomach adrenal gland, mouth esophagus, brain, liver, gall bladder,skin, bone, lymphatic system and eye, or the cancer is a hematologicalneoplasia.
 75. A method of inducing apoptosis of tumor cells in anindividual afflicted with cancer comprising administering to saidindividual an effective amount of at least one compound according toclaim 1, or a pharmaceutically acceptable salt of such a compound.
 76. Amethod according to claim 75 wherein the tumor cells are selected fromthe group of tumors consisting of tumors of the ovaries, testis, cervix,uterus, vagina, breast, prostate, lung, kidney, rectum, colon, stomachadrenal gland, mouth esophagus, brain, liver, gall bladder, skin, bone,lymphatic system and eye.
 77. A method of treating an individualafflicted with cancer, comprising administering to said individual aneffective amount of at least one conjugate according to claim 60, 63 or66.